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TM, MS
Transverse Myelopathy
                        Ann Rheum Dis 2000;59:120-4, NEJM 2010;363:564-72

 横断性脊髄症;      脊髄の全層に及ぶ障害

 – 一般人口では1.34-8/millionと稀な疾患.

 – 全年齢に生じるが, 60%は小児.
   ピークは2峰性で, 10-19yr, 30-39yr.

 – 急速(24-72hr)に進行する運動, 感覚, 自律神経障害が特徴
   対麻痺(運動, 感覚), 膀胱直腸障害. 精神症状(抑うつ)など.
   腰痛, 痙攣, 視神経障害の合併もあり.

 – 合併しやすい疾患としては,
   多発性硬化症, Viral Infection(HSV, Influenza, EBV)
   予防接種(Smallpox, Influenza), 中毒(Baclofen, PC, 鉛). 15-30%は特発性

 – 不明だが血管炎, 動脈閉塞によるNecrosisの機序が疑わしい
Ann Rheum Dis 2000;59:120-4, NEJM 2010;363:564-72

  – SLEとTransverse myelopathyの合併は稀であり, 1-2%程度
    SLEで神経精神症状を来すのは75%程度
    (抗リン脂質抗体陽性が64%とTM合併例に多い傾向)

  – 33%で前駆感染症の病歴を認める. 特に若年で多い傾向.
                                         British Journal of Hospital Medicine 2011;72:264-269

• 横断性脊椎炎の診断Criteria
                       両側性(対称性 or 非対称性)の運動, 感覚, 自律神経の中枢性障害
                                   感覚異常のLevelが明らか
                              発症から4hr~21dで進行し, Nadirを認める
                 脊髄の炎症所見; CSF細胞数増加, IgG index上昇, MRIにて造影効果認める脊髄病変

                            圧迫, 放射線後, 悪性腫瘍, 血管由来の原因を除外



   • IgG index = (CSF IgG/serum IgG) / (CSF Alb/serum Alb)
   • 診断に重要なのはMRIによる圧迫病変, 非炎症性疾患,
     悪性腫瘍の除外と, MSの評価. NMO-IgGの評価.
NEJM 2010;363:564-72
横断性脊髄炎 多発性硬化症について
TMにてチェックすべき項目
       • 自己免疫疾患ではSLE, Sjogren症候群で合併
         他にはサルコイドーシス, 感染症, 傍腫瘍症候群,
         変性疾患など.
                                                clinical pr actice
                                                                                                          N Engl J Med 2010;363:564­72.

 Table 2. Concise Differential Diagnosis and Diagnostic Testing for Transverse Myelitis.*

 Possible Cause                                                                              Diagnostic Tests

 Infection                                               Blood serologic studies; CSF culture, serologic studies, and PCR; chest radiography
                                                            and other imaging as indicated
 Systemic autoimmune or inflammatory disease             Clinical examination; serologic studies; chest and joint radiography; other tests or
                                                             imaging as indicated by history and examination
 Paraneoplastic cause                                    Chest radiography, computed tomography, or positron-emission tomography;
                                                            comprehensive serum and CSF paraneoplastic antibody panel
 Acquired CNS demyelinating disease (multiple            Brain MRI with gadolinium enhancement; CSF examination for cell count and differ-
    sclerosis, neuromyelitis optica)                         ential count, oligoclonal bands, and IgG index; tests of visual evoked potentials;
                                                             serum NMO-IgG testing
 Postinfectious or postvaccination cause                 History taking that reveals clear, recent history of infection or vaccination; serologic
                                                            confirmation of recent infection; exclusion of other causes

* CNS denotes central nervous system, CSF cerebrospinal fluid, NMO neuromyelitis optica, and PCR polymerase chain reaction.
corticosteroids, so they are no longer recommended.          flexia. Multiple sclerosis typically is monosymptomatic
Because of their ease of administration and wide avail-
ability, intravenous immunoglobulins are frequently          Table 1. Possible infective agents responsible for
• TMの原因となり得る疾患
the preferred treatment. Plasmapheresis may cause            acute transverse myelitis
hypotension and is contraindicated in patients with
underlying cardiac comorbidities (Van Koningsveld            Bacterial infections        Syphilis
and Van Doorn, 2005).
                                                                                         Abscess
Rehabilitation                                                                           Mycoplasma
Acute phase rehabilitation should include an individual-                                 Lyme disease
ized programme of gentle strengthening, involving iso-
                                                             Viral infections            Encephalomyelitis
metric, isotonic, isokinetic, and manual and progressive
resistive exercises. Rehabilitation should emphasize prop-                               Poliovirus
er limb positioning, posture and orthotics as well as                                    Herpes zoster
nutrition.                                                                               Herpes virus B
                                                                                         Rabies
Prognosis
The majority of patients will recover within weeks, but                                  Human immunodeficiency virus
30% will still have weakness after 3 years and 3% will       Autoimmune                  Systemic lupus erythematosus
relapse. The overall mortality rate is around 3–4% (El                                   Sjögren’s syndrome
Mhandi et al, 2007).
                                                                                         Sarcoidosis
Acute transverse myelitis                                                                Vasculitis
Epidemiology                                                 Vaccinations                Bacillus Calmette–Guérin
The disease has two peak incidences: between the ages                                    Smallpox
of 10–19 years, then again between the ages of
30–39 years. There have been few population-based                                        Polio
studies of acute transverse myelitis and there appears to    Other                       Parasitic infection
be no real link with any identifiable patient characteris-                               Fungal infection
tics. There is no significant seasonal or annual fluctua-
                                                                                         Acute multiple sclerosis
tion in frequency.
                                                                     British Journal of Hospital Medicine 2011;72:264-269
Case Review
                                       Ann Rheum Dis 2000;59:120-4
 600名のSLE患者中,      14名にTM(+) (2.3%)

    – 14名 + 91例のCase Reportを合わせて評価

    – TMはSLEの初発症状として出現することもあれば(39%),
      発症~5年以内に出現することも多い(42%).
      (2/14で発症 >10yrで発症している, 11yr, 21yr)

   MRIにて病変を認めるレベルはT5-T8が最も多い

    – 発症数日で上行性に感覚障害が進行.

    – 54%がTMに矛盾しない所見を示し,
      70%が何らかな異常所見を示す

   CSF所見ではWBC, Protの軽度上昇を示す

   補体は正常 ~ 軽度低下
Case Review
                                          Ann Rheum Dis 2000;59:120-4

   完全寛解を示すのは22%程度

    – 64%が不変, 14%が一部寛解を示す

    – 治療はステロイドパルス療法(MP 1g/d),
      Cyclophosphamide(1g/m2), Plasmapheresisなど報告あり

 補足; SLEに合併する多発単神経炎では,

    – 上行性の感覚障害, 左右非対称の対麻痺を来す.
      SLE, 他の血管炎症候群による血管炎が原因とされ,
      Transverse Myelopathyと酷似する病態.

    – 末梢神経伝導速度による評価で鑑別できるかもしれないが,
      大量ステロイド, Cyclophosphamideにて治療するため,
      対応は変わらない. 迅速な治療が予後にかかわる.
TMの治療
                               NEJM 2010;363:564-72


• ステロイド投与にて50-70%が反応を示す

  • 3-5dのステロイドパルスが多く行われる.

  • ステロイドに反応を示さない例では血漿交換がRescueとして行わ
    れる

  • 脱髄性疾患を合併している例では長期の免疫抑制療法が必要.
     → 再発予防効果が認められる.(Cyclophosphamide)



  • 他には対症療法;
    呼吸抑制, 痛, 筋力低下, 感覚低下, 脊髄性ショック,
    膀胱直腸障害, 精神症状への対応が必要
TM患者の長期フォロー
                                                                                                                                Arch Neurol 2012;69:357-362

• Acute partial TMと診断された85名を104.8(29.8)moフォロー
     Table 1. Clinical Data on Presentation of Patients With Multiple Sclerosis and Patients With Undetermined Etiology

                                                                 Sex, No.                                            Patients, No. (%)
                                  Age, Mean,                                           Motor           Sensory           Sphincter                 Acute         Subacute
     Group                        (Range), y              Male        Female         Symptoms         Symptoms          Symptoms                   Onset          Onset
     MS (n = 53)                 34.8 (17-54)               14              39         21 (40)         51 (96)                7 (13)               8 (15) a      45 (85) a
     Undetermined                38.6 (16-76)               13              16         10 (34)         29 (100)               3 (10)              10 (34)        19 (66)
       (n = 29)
     Combined (n = 82)           36.7 (16-76)               27              55         31 (38)         80 (98)               20 (24)              18 (22)        64 (78)

     Abbreviation: MS, multiple sclerosis.
     aP= .03 (comparison between the MS and undetermined groups determined by use of the ␹2 test).



     Table 2. Data of Spinal Cord Magnetic Resonance Imaging on Presentation

                                                                                             Patients, a No./Total No. (%)
                     Lesions, Mean
                                                         Sagittal Plane                                       Axial Plane
                       Mean Vertebral
                     (Range), Level,                                                                                                   Postero-     Centro-    Gadolinium
     Group              No.    No.            Cervical      Dorsal        Lumbar Anterior   Lateral    Posterior      Central           lateral     lateral   Enhancement
     MS (n = 53) 1.23 (0-6)       1.51       27/52 (52) 25/52 (48) 5/52 (10) 1/39 (3) 19/39 (49) b 19/39 (49) 7/39 (18) c 38/39 (97) d 26/39 (67)             26/47 (55) c
     Undetermined 1.21 (0-5)      1.33       14/29 (48) 14/29 (48) 2/29 (7) 0/26 (0) 5/26 (19) 14/26 (54) 11/26 (42) 19/26 (73) 16/26 (62)                     9/26 (35)
       (n = 29)
     Combined     1.22 (0-6)      1.42       41/81 (51) 39/81 (48) 7/81 (9) 1/65 (2) 24/65 (37)        33/65 (51) 18/65 (28) 57/65 (88) 42/65 (65)            35/73 (48)
       (n = 82)

     Abbreviation: MS, multiple sclerosis.
     a Comparisons between the MS and undetermined groups determined by use of the ␹2 test.
     b P = .03.
     c P = .02.
     d P = .011.
Arch Neurol 2012;69:357-362


  • フォロー中に62%がMSと診断され,
    感染後脊髄炎, Sjogren症候群, NMOと診断されたのが各1%.
    34%は原因不明のAPTMのまま経過.

  • 後々MSと診断される例は, CSF oligoclonal bandsと
    MRIにて脳病変を認める例が多い.
                                                                             APTM                       MS                              OR
                                     Oligoclonal bands                         38%                      92%                 15.76[2.95-84.24]
                                         脳MRI所見                                27%                      87%                  7.74[2.42-24.74]

Table 3. Results of Paraclinical Examination at Presentation

                                                                      Patients, No./Total No.
                                       Brain MRI Results                                               CSF Analysis
                                                            Fulfilling           Protein Level,            Cell Count,
                           No               Ն1             Barkhof et            Mean (Range),            Mean (Range),          Presence         Abnormal
Group                    Lesions          Lesions          al15 criteria              g/dL                  cells/mm3             of OCBs            VEPs
MS                     7/52 (13) a    45/52 (87) b         28/52 (54) c          4.5 (1.6-9.2)             13.5 (0-87)         43/47 (91) d     20/46 (43) e
Undetermined          19/26 (73)       7/26 (27)            0/26 (0)             5.2 (1.9-14.3)            9.38 (0-133)        10/26 (38)        1/26 (4)
Combined              26/78 (33)      52/78 (67)           28/78 (36)            4.8 (1.6-14.3)           11.42 (0-133)        53/73 (73)       21/72 (29)

 Abbreviations: CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis; OCBs, oligoclonal bands; VEPs, visual evoked potentials.
SI conversion factor: To convert protein to grams per liter, multiply by 10.0.
a P = 5 ϫ 10−7.
b P = 5.43 ϫ 10−7.
c P = 9 ϫ 10−6.
d P = 4 ϫ 10−6.
e P = .001.
Multiple Sclerosis
                             Neurology" 2012;79 (Suppl 2):S1–S15


• CNSの炎症性, 脱髄性変化を来す慢性疾患.

  • 主に脱髄とAxonの損傷が認められる.
    障害部位はCNS全般. 白質, 小脳, 脳幹, 脊髄, 視神経.

  • 症状は様々で, 単独の症状∼複合症状.
    認知障害, 怠感, 運動障害, 歩行障害, 視覚障害,
    感覚障害, 膀胱直腸障害, 神経性 痛など.

  • 病状の進行形式も様々.
    急速に増悪, 寛解を繰り返し, 徐々に障害を残す (歩行障害など.)

• MSの平均年齢は30歳. 70%が20-40歳で発症する.

  • 男女比は1:3と女性に多い.
Neurology" 2012;79 (Suppl 2):S1–S15


• MSのパターン;

  • Clinically isolated syndrome(CIS); MS様症状の初回発作.
    (視神経炎, 脊髄炎, 脳幹症状). 空間的, 時間的解離の要素は無い.

  • Relapsin-remitting MS(RRMS); 増悪と寛解を繰り返す.
    寛解期には症状は完全に改善する. MSの80-85%が初期にはRRMS

  • Primary progressive MS(PPMS); 初回発作から徐々に増悪する経過.
    軽快は認めるが, 完全には良くならず, 全体的に増悪する経過.
    MSの10-15%が当てはまる.

  • Secondary progressive MS(SPMS); RRMSを経て, 増悪に移行する
    経過を示す. RRMSの大半がこのパターンに移行する.

  • Progressive relapsing MS; 寛解, 増悪を繰り返しながら,
    徐々に増悪するタイプ. PPMSとの区別は難しい.
Neurology" 2012;79 (Suppl 2):S1–S15


• 他のMS suptype

   • Benign MS; RRMSで10年以上EDSS score<3.0を満たすもの
     (Expanded Disability Status Scale) 

   • Single-attack progressive MS; PPMSのSubtype

   • Malignant or fulminant MS; 急速進行性のMS.
     数ヶ月で重度の障害を来す.

   • Transitional MS; RRMSとSPMSの移行期.
MSの画像所見
                                  Neurology" 2012;79 (Suppl 2):S1–S15


• 白質, 小脳, 脳幹, 脊髄病変がDIS, DITで認める.

  • DIS; Dissemination in space; 連続性のない病変をMRIにて確認.
     よく使用されるのはMcDonald criteria(次スライド)

  • DIT; Dissemination in time; フォローMRIにて
     T2 high, Ga造影病変が新規に出現していることで定義.

  • 上記+典型的なMRI所見を認めればMSと診断する事が多い.
Articles                                                MSの画像所見
                                                                                                                                                        Lancet Neurol 2011; 10: 1065–73

               • 各診断Criteriaの感度, 特異度
                 (284名の疑い患者の3.9yフォロー. 内20%が後にMS. )
                                   ≥1 periventricular lesion and 2005 McDonald DIS*2                      Paediatric MS†5                    Paediatric MS-ADEM‡6                KIDMUS§7
                                   ≥1 T1-hypointense lesions
 Sensitivity                         48/57 (84%)                         32/57 (56%)                        42/57 (74%)                        54/57 (95%)                         23/57 (40%)
 Specificity                         212/227 (93%)                      164/227 (72%)                      154/227 (68%)                       205/227 (90%)                      222/227 (98%)
 Positive predictive value           48/63 (76%)                         32/95 (34%)                        42/115 (37%)                       54/76 (71%)                         23/28 (82%)
 Negative predictive value          212/221 (96%)                      164/189 (87%)                      154/169 (91%)                       205/208 (99%)                      222/256 (87%)
 Youden’s J                           0·77                                0·28                               0·42                               0·85                                0·38

Data are number (%). DIS=dissemination in space. MS=multiple sclerosis. ADEM=acute disseminated encephalomyelitis. KIDMUS=kids with multiple sclerosis. *Three of the following lesion patterns: nine or
               McDonald DIS                                        Paediatric MS                                  Paediatric MS-ADEM                                                   KIDMUS
more T2 lesions or one or more gadolinium lesion, three or more periventricular lesions, one or more juxtacortical lesion, or one or more infratentorial lesion. †Two of the following lesion patterns: five or more
T2 lesions, two or more periventricular lesions, or one or more brainstem lesion. ‡Two of the following lesion patterns: two or more periventricular lesions, one or more T1-hypointense lesions, absence of diffuse
       以下の3つ以上を満たす                                          以下の2つ以上を満たす                                          以下の2つ以上を満たす                                              以下の2つ以上を満たす
bilateral pattern. §Two of the following lesion patterns: Dawson fingers (lesions perpendicular to the long axis of the corpus callosum) and one or more well defined lesion.

Table 4: Comparison of published MRI criteria with proposed predictive parameters for diagnosis of multiple sclerosis
    ≥9箇所のT2病変を認める                                       ≥5箇所のT2病変                                ≥2箇所の脳室周囲病変                                                                  Dawson fingers*
    ≥1箇所のgadoliium病変             ≥2箇所の脳室周囲病変                       ≥1箇所のT1で低信号病変                            ≥1箇所の明瞭な病変
    ≥3箇所の脳室周囲病変 unchanged when contrast-enhancement was 両側性パターン無しobtained more than 12 months after
                 remained           ≥1箇所の脳幹病変                   びまん性, basis of MRI scans
                 added. After adjustment for onset age and sex, contrast- onset. The diagnostic usefulness of one or more
  ≥1箇所のJuxtacortical lesion lesions were not significantly associated with periventricular lesions and one or more T1-hypointense
                 enhancing
                 MS diagnosis.                                                    * Dawson fingers; 脳梁の垂直方向性の病変
                                                                            lesions in the entire cohort (table 4) did not differ from the
    ≥1箇所のテント下病変    The presence of both one or more periventricular lesions performance of these parameters in the 108 participants
                 and one or more T1-hypointense lesions at baseline was who had annual MRIs (sensitivity 83%, specificity 92%,
                 strongly predictive of MS (hazard ratio 34·27, 95% CI PPV 68%, NPV 97%) or in the 176 children who did not
                 16·69–70·38, figure 2). 48 of 57 children subsequently have annual MRI scans (sensitivity 85%, specificity 94%,
Neurology" 2012;79 (Suppl 2):S1–S15
  Table 1       Summary of 2005 and 2010 McDonald criteriaa

                                             Additional data needed for MS diagnosis


  Clinical presentation                      2005                                                  2010

  ‡2 attacks; objective clinical evidence    None                                                  None
  of ‡2 lesions or objective clinical
  evidence of 1 lesion with reasonable
  historical evidence of a prior attack

  ‡2 attacks; objective clinical evidence    Dissemination in space demonstrated by:               Dissemination in space according to new definition:
  of 1 lesion                                 MRI (Barkhof-Tintoré criteria) or                    $1 lesion in 2 of 4 characteristic areas
                                              $2 MRI-detected lesions consistent with               (periventricular, juxtacortical, infratentorial,
                                               MS plus positive CSF or                               or spinal cord) or
                                              A further clinical attack implicating a different    A further clinical attack implicating a different CNS site
                                               CNS site

  1 attack; objective clinical evidence      Dissemination in time demonstrated by:                Dissemination in time according to new definition:
  of ‡2 lesions                               MRI (new T2 lesion after baseline scan 30 d          New T2 and/or Gd-enhancing lesion at follow-up or
                                               after initial event or Gd-enhancing 3 mo             Simultaneous presence of enhancing and nonenhancing
                                               after event) or                                       lesions or
                                              A further clinical attack                            A further clinical attack

  1 attack; objective clinical evidence      Dissemination in space and time as above              Dissemination in space and time according to new definitions
  of 1 lesion (CIS)

  Insidious neurologic progression           1 y of disease progression plus 2 of:                 Same as in 2005 criteria, but use new DIS definitions
  suggestive of MS (PPMS)                     Positive brain MRI
                                              Positive spinal cord MRI
                                              Positive CSF

Abbreviations: CIS 5 clinically isolated syndrome; DIS 5 dissemination in space; Gd 5 gadolinium; MS 5 multiple sclerosis; PPMS 5 primary progressive MS.
a
  Adapted from Polman et al., 2011,15 with permission.




                                  CIS and MS has been moving toward earlier and                    CLINICAL IMPLICATIONS OF THE 2010 UPDATE
                                  earlier diagnosis of MS.                                         Widening the window. One of the most important
there is a historical suggestion of an earlier relapse?       standard in this population.

                                                                                  Neurology 2012;79 (Suppl 2):S1–S15

  Figure      Recommended algorithm for diagnosis of inflammatory demyelinating disease




ADEM 5 acute disseminated encephalomyelitis; CIS 5 clinically isolated syndrome; DIS 5 dissemination in space; DIT 5
dissemination in time; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica. Adapted from Miller et al.32 (by permission of
Sage Publications, © 2008).

Neurology 79 (Suppl 2)   December 4, 2012
MSの治療
                                                          Mt Sinai J Med 78:176–191, 2011.


• MSの治療は疾患自体に対する治療(DMTs)と対症療法がある    MOUNT SINAI JOURNAL OF MEDICINE
  (Disease-modifying therapeutics;DMTs) 
                                        Table 1. Primary, Secondary, and Tertiary Symptoms in
                                        Multiple Sclerosis.
    • 症状も急性症状, 亜急性(6mo),
                                        Symptom                 Primary   Secondary    Tertiary
      慢性(6mo)があり,                      Weakness                  X           X
      また, 脱髄自体による症状,                    Sensory loss
                                        Vision loss
                                                                  X
                                                                  X
      その症状に随伴するものと,                     Diplopia
                                        Impaired balance
                                                                  X
                                                                  X           X
      様々な現れ方がある.                        Incoordination
                                        Sexual dysfunction
                                                                  X
                                                                  X           X             X
                                        Bladder symptoms          X           X
                                        Bowel issues              X           X
                                        Cognitive dysfunction     X           X             X
                                        Fatigue                   X           X             X
                                        Depression                X           X             X
                                        Anxiety                   X           X             X
                                        Social isolation                      X             X
                                        INO/nystagmus             X
                                        Contractures                          X
                                        Vertigo                   X
                                        Speech issues             X
                                        Swallow issues            X
                                        Pain                      X           X             X
                                        Spasticity                X           X

                                        Abbreviations: INO, internuclear ophthalmoplegia.
Mt Sinai J Med 78:176–191, 2011.


• 急性期治療はステロイド.

  • 症状に応じてmPSLパルス, PSL 1mg/kg/dが選択される.
    効果不十分の場合は血漿交換も考慮する.

  • ステロイド投与経路はIV, POどちらも効果は同等.

• MSの寛解期, 安定期には増悪予防が重要となる.
  その為の薬剤がDMTsであり, 現在最も研究が盛んな分野.
62
                                                       DMTs
                                                      J. DERWENSKUS: DISEASE-MODIFYING TREATMENT OF MULTIPLE SCLEROS

                                                                    MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011
     Table 1.     FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

     Medication                            Dose        Route        Frequency        Approved in US   Pregnancy Category

     Fingolimod (Gilenya)                 0.5 mg        Oral          Daily              2010                 C
     Glatiramer acetate (Copaxone)         20 mg        SC            Daily              1996                 B
     IFNβ-1a (Avonex)                      30 µg        IM         1× weekly             1996                 C
     IFNβ-1b (Betaseron)                  0.25 mg       SC       Every other day         1993                 C
     IFNβ-1b (Extavia)                    0.25 mg       SC       Every other day         2009                 C
     IFNβ-1a (Rebif)                     22, 44 µg      SC         3× weekly             2002                 C
     Mitoxantrone (Novantrone)           12 mg/m2        IV      Every 3 months          2000                 D
     Natalizumab (Tysabri)                300 mg         IV         Monthly            2004/2006              C

     Abbreviations: IM, intramuscular; IV, intravenous; SC, subcutaneous; US, United States.


            • DMTsはMSの増悪を予防する薬剤. FDAでは8つが承認.
     likely will change as more effective therapies become          in MS. However, more recently the effect of IFN-β on
     available.                                                     T helper 17 has been discovered to also be playing
                                                                    a role.2
          The advent of disease-modifying
          therapy has changed the focus
          of managing multiple sclerosis                            Interferon Pivotal Trials
          from the treatment of acute                               The first pivotal study leading to FDA approval of
          exacerbations to the prevention                           IFN-β in relapsing-remitting MS (RRMS) was reported
                                                                    by the IFNB Multiple Sclerosis Study Group.3 This
          of new disease activity. There
exacerbations to the prevention  IFN-β in relapsing-remitting MS (RRMS) was reported
                                   MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011
                                    by the IFNB Multiple Sclerosis Study Group.3 This
   of new disease activity. There   was a randomized, double-blind, placebo-controlled
   are currently 8 FDA-approved     study of 372 patients with clinically definite MS.
• β-Interferon;this purpose
   therapies for 機序は未だ詳しくは不明だが,     Patients were randomized to either placebo or 1.6 or 8
   MS予防効果が認められている.2IFN-β-1b third-year double-blindevery other was
   and numerous others in clinical  MIU
                                    for years. A
                                                   given as a SC injection
                                                                           extension
                                                                                       day

   trials.                          included as part of this study. There was a significant
     • T cellがCNSへ移行するのを予防することで予防する. rate (ARR) of
                                    reduction in the annualized relapse
                                    almost 34% in the higher-dose IFN-β-1b group, which
             BETA-INTERFERONS                            was the primary outcome measure (Figure 1). There
         • RRMS 372名のDB-RCTでは, 高用量IFN-β-1b群で有意な 1.17 attacks
                                                         were 1.27 attacks per year for placebo,
                                                         per year for the 1.6 MIU group, and 0.84 attacks
            再燃頻度の低下が認められた. per year34%the 8 MIU group (placebo versus 8
Beta-interferon (IFN-β) was the first class of therapy     ARR for
approved to treat MS. IFN-β-1b (Betaseron) given
subcutaneously (SC) every other 1.6MIU 1.17 vs 8MIU 0.84回/yr)
            (Placebo 1.27 vs day was approved
by the FDA in 1993. Since then, 3 additional IFN-β
have been approved in the United States: IFN-β-1a
         • PRISMS trialでは,
(Avonex), given as a weekly intramuscular (IM) injec-
            IFN-β-1a 22µg-44µg 3回/wkで
tion, in 1996; IFN-β-1a (Rebif), given as a SC injection
3× weekly, in 2002; and IFN-β-1b (Extavia), given as
            有意に再発率を低下.
a SC injection every other day, in 2009.
      Although the exact mechanism of action is
unknown, IFN-β drugs likely have multiple effects
on the • IFNの副作用は,
         immune system.1 The effects in the periph-
            Flu-like症状, 75%で認められる
ery include inhibition of antigen presentation, and
at the blood-brain barrier there is down-regulation
            75%が3moで減弱, production of
of adhesion molecules and decreased 消失.
matrix metalloproteinases. This limits the entry of
T cells into the central nervous system (CNS). Clas-
sically the emphasis has been on IFN-β causing a Fig 1. Kaplan-Meier analysis showing the probability of
                                                         remaining exacerbation-free in the first 2 years of the study
shift from T helper 1 to T helper 2 cells, creating an comparing 2 different doses of IFN-β to placebo.
anti-inflammatory milieu as an important mechanism
MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011


• Glatiramer acetate; 未承認

    • RRMS 251名のRCTでは, 2年後の再年率は有意に低下.
      Glatiramer 20mg/d SC vs Placebo; (1.19 vs 1.68, p=0.007).
    • 副作用は少なく, 投与部位の発赤程度.

• Mitoxantrone; ノバントロン®

    • AML, 前立腺癌に対する抗癌剤.
                           MOUNT SINAI JOURNAL OF MEDICINE
      B-cellの抑制, Mφによる脱髄を抑制する.

    • MIMS trial; PPMS 194名のDB-RCT
      (Placebo vs MIT 5, 12mg/m2 3mo)
    • 2年継続し, 症状, 再燃を評価.
        12mg/m2群で有意に頻度低下.
       @36mでも効果持続しており,
       薬剤中止後も効果が期待できる.

    • MITの極量は140mg/m2 (積算)
                                             Fig 4.   Time to first treated relapse.
MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011


• Natalizumab; 未承認, α4 β1 integrinのα4 subunitを阻害.

   • CNSへのLyの移行を阻害する作用を示す.

   • AFFIRM study; RRMS 942名のRCT.
      natalizumab 300mg q4wk vs Placeboで2y継続.

     • 開始後1年間での再燃率は0.26 vs 0.81, p0.001と
       有意にnatalizumabで再燃リスクが軽減.

   • SENTINEL study; RRMSでIFN-β-1a 30µg/wk投与下でも
      再燃を認めた1171名のRCT.
      natalizumab追加群 vs IFN継続群で再燃率を比較.

     • 再燃率は0.38 vs 0.82と有意で併用群で低下を認めた.

   • Natalixumabではmultifocal leukoencephalopahtyのリスクがあり,
      発症率は1/1000との報告があり, 注意が必要.
phase III clinical trials. The FTY720 Research Evaluat-
                                                                                  MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011
                                        ing Effects of Daily Oral Therapy in Multiple Sclerosis
                                        (FREEDOMS) trial was a randomized, double-blind,
                                        placebo-controlled study of 1272 patients comparing
           • Fingolimod; ジレニア, イムセラ                                                 ®
                                        2 doses of fingolimod (0.5 mg or 1.25 mg) versus
                                        placebo taken once daily for 24 months.37 Included
                                        subjects were ages 18–55 years and had RRMS.
                   • RRMSに対する経口投与可能な薬剤. Patients were excluded if they had been treated with
                                        steroids within 30 days of randomization, had an
                     Sphingosine-1-phosphate-Rの調節剤であり,
                                        active infection, or had history of macular edema,
                                        diabetes mellitus, immune suppression, or clinically
                     リンパ節からリンパ球が放出されるのを抑制する.
                                        significant systemic disease. Standard DMT such as
                                        IFN-β or glatiramer acetate was stopped ≥3 months
                       リンパ球が低下し, CNSでの脱髄が抑制される機序.
                                        J. DERWENSKUS: DISEASE-MODIFYING TREATMENT OF MULTIPLE SCLEROSIS
                                        before randomization. Patients had neurologic exam-
                                        inations performed every 3 months, and MRI scans
 he approval of fingolimod was based on 2were done at 6, 12, and 24 months. The study met
                   • FREEDOMS trial; RRMS患者1272名のDB-RCT.
 III clinical trials. The FTY720 Research Evaluat- outcome measure with a reduction in the
                                        its primary
fects of Daily Oral Therapy in Multiple Sclerosis0.18 in the 0.5-mg group and 0.16 in the
                                        ARR to
                      Fingolimod 0.5mg, 1.25mg vs Placebo, 24mo継続群で比較.
 DOMS) trial was a randomized, double-blind, group, respectively, compared with 0.40 in
                                        1.25-mg
bo-controlled study of 1272 patients comparing
                                        the placebo group. This corresponded to a relative
es of fingolimod (0.5 mg or 1.25 mg) versus of 54% and 60% in the ARR (P  0.001).
                                        reduction
                        • 0.5mg, 1.25mg群はPlaceboと比較して再燃率, 増悪が少ない.
bo taken once daily for 24 months.37 Other secondary outcomes also favored fingolimod.
cts were ages 18–55 years and had RRMS.
                                         Included

                          Dose間では有意差無く, 0.5mg/dで十分.
 ts were excluded if they had been treated with
                                           The FREEDOMS trial was a
dsDwithin-MODIFYING Trandomization, ULTIPLE SCLEROSIS
 : ISEASE 30 days of REATMENT OF M had an
                                           randomized, double-blind,
  infection, or had history of macular edema,
 es mellitus, immune suppression, or clinically
                                           placebo-controlled study of 1272
 cant systemic disease. Standard DMT such as
                                           patients comparing 2 doses of
  or glatiramer acetate was stopped ≥3 months
e randomization. Patients had neurologic exam-
                                           fingolimod (0.5 mg or 1.25 mg)
ns performed every 3 months, and MRI scans
 done at 6, 12, and 24 months. The study versus placebo taken once daily
                                            met
mary outcome measure with a reduction in the 24 months. The study showed a
                                           for
 o 0.18 in the 0.5-mg group and 0.16 in the
                                           reduction in the ARR to 0.18 in
mg group, respectively, compared with 0.40 in
 acebo group. This corresponded to a relative 0.5-mg group and 0.16 in the
                                           the
tion of 54% and 60% in the ARR (P  0.001).
                                           1.25-mg group, respectively,
  secondary outcomes also favored fingolimod.
                                    compared with 0.40 in the placebo
The FREEDOMS trial was a
N Engl J Med 2010;362:387-401.

  • FREEDOMS study; 18-55歳のRRMS 1272名のDB-RCT.

        • EDSS score 0-5.5で, 過去1年以内に1回以上,
           過去2年以内に2回以上の再燃を繰り返している患者群.

        • Fingolimod 0.5mg vs 1.25mg vs Placeboに割り付け, 24m継続し,
          各群の再燃率を比較.

  • アウトカム; 治療を24m継続できたのは81.2%.
     中断率は0.5mg群で18.8%, 1.25mg群で30.5%, Placeboで27.5%.
     Outcome             1.25mg             0.5mg           Placebo         1.25 vs P          0.5 vs P
      再年率/y           0.16[0.13-0.19]   0.18[0.15-0.22]   0.40[0.34-0.47]    P0.001           P0.001
    再燃(-)率 @24m       74.7%[70.4-78.9] 70.4%[66.0-74.8] 45.6%[40.7-50.6] HR0.38[0.30-0.48] HR0.48[0.39-0.61]
   障害の進行(-)率          83.4%[79.7-87.1] 82.3%[78.6-86.1] 75.9%[71.7-80.2] HR0.68[0.50-0.93] HR0.70[0.52-0.96]
  Ga造影(+) 数@24m           0.2±1.1          0.2±0.8           1.1±2.4          0.001            0.001
Ga造影(+)病変(-)率@24m         89.8%             89.7%             65.1%           0.001            0.001
T2病変 増悪, 新規(-) @24m       51.9%             50.5%             21.2%           0.001            0.001


        • Fingolimod群の方が有意に再年率, 新規病変の出現が軽減.
           脳実質量の比較でも有意に低下が少なくなる.
N Engl J Med 2010;362:402-15.


 • TRANSFORMS study; RRMS 1292名のDB-RCT.

      • Inclusion criteriaはFREEDOMS studyと同様.

      • Fingolimod 1.25mg vs 0.5mg vs INF-β-1a 30µg/wkに割り付け,
        12mo継続し, 再年率を比較.

 • アウトカム; 治療を継続できたのは89%.
    Outcome          1.25mg             0.5mg              IFN          1.25 vs IFN       0.5 vs IFN
    再年率/y         0.20[0.16-0.26]   0.16[0.12-0.21]   0.33[0.26-0.42]     0.001            0.001
  再燃(-) 率@12mo    79.8%[75.9-83.7] 82.6%[79.0-86.3] 69.3%[64.8-73.8]      0.001            0.001
 T2病変増悪, 新規 (-)       48.0%             54.8%             45.7%            0.37              0.01
Ga造影病変増悪, 新規(-)       91.2%             90.1%             80.8%           0.001            0.001



      • FingolimodはIFN-β-1aよりも再燃予防効果が高い.
         また, 病変の出現, 増悪リスク, 神経機能増悪リスクも低い.
Table 3. Adverse Events in the Safety Population, According to Study Group.                                                 Table 3. (Continued.)

Event                                                                     Fingolimod                   Placebo (N = 418)    Event                                                                       Fingolimod                   Placebo (N = 418)
                                                          1.25 mg (N = 429)     0.5 mg (N = 425)                                                                                       1.25 mg (N = 429)      0.5 mg (N = 425)
                                                                                 no. of patients (%)                                                                                                           no. of patients (%)
All events                                                                                                                  Psychiatric disorders
At least one adverse event                                    404 (94.2)           401 (94.4)             387 (92.6)            Depression                                                   26 (6.1)                33 (7.8)            28 (6.7)
Any adverse event leading to discontinuation of study          61 (14.2)               32 (7.5)            32 (7.7)             Insomnia                                                     16 (3.7)                21 (4.9)            25 (6.0)
          drug*
                                                                                                                            Hypercholesterolemia                                             26 (6.1)                24 (5.6)            26 (6.2)
Any serious adverse event                                      51 (11.9)               43 (10.1)           56 (13.4)
                                                                                                                            Weight increase                                                  14 (3.3)                14 (3.3)            22 (5.3)
Death                                                           1 (0.2)                 0                    2 (0.5)
                                                                                                                            Vertigo                                                          18 (4.2)                18 (4.2)            21 (5.0)
Frequent or special-interest adverse events†
                                                                                                                            Macular edema                                                     7 (1.6)                 0                    0
Infections
                                                                                                                            Serious adverse events¶
   Upper respiratory tract infection                          206 (48.0)           212 (49.9)             211 (50.5)
                                                                                                                            Cardiovascular disorders
        Nasopharyngitis                                       112 (26.1)           115 (27.1)             115 (27.5)
        Sinusitis                                              27 (6.3)                28 (6.6)            19 (4.5)             Bradycardia                                                   3 (0.7)                 4 (0.9)              1 (0.2)
        Pharyngitis                                            25 (5.8)                27 (6.4)            24 (5.7)             Myocardial infarction                                         0                       0                    2 (0.5)
        Rhinitis                                               18 (4.2)                25 (5.9)            25 (6.0)         Neoplasms
   Influenza virus infection                                   40 (9.3)                55 (12.9)           41 (9.8)             Basal-cell carcinoma                                          1 (0.2)                 4 (0.9)              3 (0.7)
   Lower respiratory tract or lung infection                   49 (11.4)               41 (9.6)            25 (6.0)             Breast cancer                                                 1 (0.2)                 0                    3 (0.7)
        Bronchitis                                             39 (9.1)                34 (8.0)            15 (3.6)             Malignant melanoma                                            1 (0.2)                 0                    1 (0.2)
        Pneumonia                                               8 (1.9)                 4 (0.9)              3 (0.7)            Bowen’s disease                                               1 (0.2)                 0                    0
   Herpesvirus infection‡                                      25 (5.8)                37 (8.7)            33 (7.9)             Cervical carcinoma, stage 0                                   0                       0                    1 (0.2)
   Urinary tract infection                                     21 (4.9)                34 (8.0)            47 (11.2)            Endometrial cancer                                            0                       0                    1 (0.2)
Nervous system disorders                                                                                                        Prostate cancer                                               0                       0                    1 (0.2)
   Headache                                                   114 (26.6)           107 (25.2)              96 (23.0)        Nervous system disorders
   Dizziness                                                   30 (7.0)                31 (7.3)            23 (5.5)             MS relapse                                                    3 (0.7)                 4 (0.9)              1 (0.2)
   Paresthesia                                                 17 (4.0)                23 (5.4)            18 (4.3)             Epilepsy                                                      2 (0.5)                 0                    0
Abnormal laboratory liver-function test§                       80 (18.6)               67 (15.8)           21 (5.0)             Headache                                                      2 (0.5)                 0                    0
Fatigue                                                        47 (11.0)               48 (11.3)           45 (10.8)        General disorders
Musculoskeletal disorders                                                                                                       Chest pain                                                    0                       4 (0.9)              2 (0.5)
   Back pain                                                   45 (10.5)               50 (11.8)           29 (6.9)         Macular edema                                                     3 (0.7)                 0                    0
   Arthralgia                                                  27 (6.3)                30 (7.1)            33 (7.9)         Laboratory evaluation
   Pain in extremity                                           24 (5.6)                28 (6.6)            28 (6.7)             Abnormal liver-function test                                  2 (0.5)                 0                    1 (0.2)
Gastrointestinal disorders                                                                                                      Lymphopenia                                                   2 (0.5)                 0                    0
   Diarrhea                                                    40 (9.3)                50 (11.8)           31 (7.4)         Depression                                                        2 (0.5)                 0                    1 (0.2)
   Nausea                                                      38 (8.9)                38 (8.9)            36 (8.6)         Musculoskeletal disorders
Respiratory disorders                                                                                                           Back pain                                                     0                       2 (0.5)              1 (0.2)
   Cough                                                       37 (8.6)                43 (10.1)           34 (8.1)
                                                                                                                                Intervertebral disk protrusion                                0                       0                    2 (0.5)
   Dyspnea                                                     23 (5.4)                30 (7.1)            19 (4.5)
                                                                                                                            Abortion                                                          0                       0                    3 (0.7)
   Oropharyngeal pain                                          17 (4.0)                29 (6.8)            29 (6.9)
                                                                                                                            Urinary tract infection                                           0                       2 (0.5)              0
Blood and lymphatic system disorders
   Leukopenia                                                  27 (6.3)                12 (2.8)              1 (0.2)       * “Any adverse event leading to discontinuation of the study drug” includes events occurring in patients whose primary
                                                                                                                             or secondary reason for discontinuing the study drug was an adverse event (including abnormal laboratory findings).
   Lymphopenia
Cardiovascular disorders
                                                               23 (5.4)                15 (3.5)              2 (0.5)
                                                                                                                             FREEDOMSの副作用;
                                                                                                                           † “Frequent adverse events” includes those reported in 5% or more of patients in any group.
                                                                                                                           ‡ The terms used to report herpesvirus infection included oral herpes, herpesvirus infection, herpes simplex virus infec-
   Hypertension                                                27 (6.3)                26 (6.1)            16 (3.8)          tion, herpes zoster, genital herpes, and herpes dermatitis.
   Bradycardia, bradyarrhythmia, or sinus bradycardia
   Atrioventricular block
                                                               14 (3.3)                 9 (2.1)              3 (0.7)
                                                                                                                             不整脈と黄斑浮腫のチェックは大事
                                                                                                                           § The terms used to report an abnormal laboratory liver-function test included increased levels of alanine aminotrans-
                                                                                                                             ferase, aspartate aminotransferase, γ-glutamyltransferase, hepatic enzyme, and aminotransferases, and abnormal
                                                                                                                             liver-function tests or γ-glutamyltransferase levels.
        First degree                                            5 (1.2)                 2 (0.5)              2 (0.5)       ¶ “Serious adverse events” includes those reported in two or more patients in any group or of special interest.
                                                                                                                             “MS relapse” includes both events related to the worsening of multiple sclerosis (MS) and MS relapses. See the
        Second degree                                           1 (0.2)                 0                    1 (0.2)
                                                                                                                             Supplementary Appendix for further details.              N Engl J Med 2010;362:387-401.
Table 3. Adverse Events and Serious Adverse Events (Safety Population).*                                                  Table 3. (Continued.)

                                                                                                    Interferon Beta-1a                                                                                                         Interferon Beta-1a
Event                                                                   Fingolimod                       (N = 431)        Event                                                                    Fingolimod                       (N = 431)
                                                       1.25 mg (N = 420)       0.5 mg (N = 429)                                                                                   1.25 mg (N = 420)       0.5 mg (N = 429)
                                                                              no. of patients (%)                                                                                                        no. of patients (%)
All adverse events                                                                                                        Serious adverse events
Any event                                                 380 (90.5)            369 (86.0)             395 (91.6)         Any serious event                                            45 (10.7)             30 (7.0)                25 (5.8)
Any event leading to discontinuation of a study drug        42 (10.0)            24 (5.6)                16 (3.7)         Death                                                         2 (0.5)†                0                     0
Most frequently reported adverse events                                                                                   Cardiovascular disorder

Infection                                                                                                                     Bradycardia or sinus bradycardia                         10 (2.4)                 2 (0.5)               0

   Nasopharyngitis                                          93 (22.1)            88 (20.5)               88 (20.4)            Atrioventricular block

   Upper respiratory tract infection                        36 (8.6)             31 (7.2)                27 (6.3)                 Second degree                                         3 (0.7)                 1 (0.2)               0

   Influenza                                                28 (6.7)             29 (6.8)                32 (7.4)                 First degree                                          2 (0.5)                 1 (0.2)               0
                                                                                                                          Infection
   Urinary tract infection                                  24 (5.7)             26 (6.1)                22 (5.1)
                                                                                                                              Appendicitis                                              2 (0.5)                 0                     2 (0.5)
   Herpesvirus infection                                    23 (5.5)                 9 (2.1)             12 (2.8)
                                                                                                                              Herpesvirus infection                                     3 (0.7)                 1 (0.2)               1 (0.2)
Nervous system disorder
                                                                                                                          Neoplasm
   Headache                                                 96 (22.9)            99 (23.1)               88 (20.4)
                                                                                                                              Basal-cell carcinoma                                      2 (0.5)                 3 (0.7)               1 (0.2)
   Dizziness                                                23 (5.5)             24 (5.6)                21 (4.9)
                                                                                                                              Melanoma (including in situ)                              0                       3 (0.7)               0
General disorder
                                                                                                                              Breast cancer (including in situ)                         2 (0.5)                 2 (0.5)               0
   Fatigue                                                  59 (14.0)            44 (10.3)               45 (10.4)
                                                                                                                          Respiratory disorder
   Pyrexia                                                  15 (3.6)             18 (4.2)                77 (17.9)
                                                                                                                              Dyspnea                                                   2 (0.5)                 0                     0
   Influenza-like illness                                   15 (3.6)             15 (3.5)              159 (36.9)
Gastrointestinal disorder                                                                                                * Listed are all adverse events that occurred in more than 5% of patients in any study group (with the exception of lym-
                                                                                                                           phocytopenia), in decreasing order of total frequency. Listed serious adverse events occurred in at least two patients in
   Diarrhea                                                 35 (8.3)             32 (7.5)                21 (4.9)          any study group.
                                                                                                                         † The two deaths in the group that received fingolimod at a dose of 1.25 mg were caused by disseminated primary vari-
   Nausea
Musculoskeletal disorder
                                                            28 (6.7)             40 (9.3)                29 (6.7)
                                                                                                                           TRANSFORMSの副作用;
                                                                                                                           cella zoster infection and herpes simplex encephalitis.

   Back pain                                                27 (6.4)             26 (6.1)                23 (5.3)
   Limb pain                                                20 (4.8)             21 (4.9)                28 (6.5)          徐脈, this is one of the largest studies in- further evaluation in the 2-year, placebo-controlled
                                                                                                                           Although 不整脈, 帯状疱疹のリスクが上昇.
                                                                                                                         volving patients with multiple sclerosis to date, phase 3 trials.
   Arthralgia                                               17 (4.0)             12 (2.8)                24 (5.6)
                                                                                                                         a potential shortcoming is that rare or late-appear-
   Myalgia                                                  14 (3.3)             14 (3.3)                44 (10.2)         基底細胞癌やメラノーマ,
                                                                                                                         ing adverse events may not have been detected
                                                                                                                                                                                 Supported by Novartis Pharma.
                                                                                                                                                                                 Presented in part at the annual meetings of the American
Respiratory disorder                                                                                                     because of their low incidence and the 1-year study  Academy of Neurology, Seattle, in April 2009, and of the Euro-
                                                                                                                                                                              pean Committee for Treatment and Research in Multiple Sclero-
   Cough                                                    30 (7.1)             20 (4.7)                16 (3.7)          乳癌のリスクにもなり得る
                                                                                                                         duration. Integrated analyses of data from other sis, Dusseldorf, Germany, in September 2009.
                                                                                                                         phase 3 studies and from the extensions of the          Dr. Cohen reports receiving consulting fees from Biogen Idec,
   Dyspnea                                                  22 (5.2)                 8 (1.9)              7 (1.6)
                                                                                                                         phase 2 and phase 3 studies will help refine the     Novartis, EMD Serono, and Teva, lecture fees from Sanofi-
Neoplasm                                                                                                                                                                      Aventis and Waterfront Media, and research support from Gen-
                                                                                                                         safety profile of fingolimod, including a possible zyme, Novartis, and Teva; Dr. Barkhof, receiving consulting fees
   Melanocytic nevus                                        42 (10.0)            28 (6.5)                24 (5.6)        increase in the risk of cancer.                      from Bayer Schering, Serono, Sanofi-Aventis, AstraZeneca, Ge-
Psychiatric disorder                                                                                                       定期的なLabのチェック,
                                                                                                                            An oral treatment option for relapsing–remit- nentech, Novartis, Biogen Idec, Lundbeck, Talecris, Roche, Wy-
                                                                                                                                                                              eth, and MediciNova and lecture fees from Bayer Schering and
   Depression                                               18 (4.3)             21 (4.9)                32 (7.4)        ting multiple sclerosis is highly desirable to im- Serono; Dr. Comi, receiving consulting fees from Merck Serono,
Vascular disorder                                                                                                          眼科診察,VZVの注意, 癌の注意が必要.
                                                                                                                         prove convenience, diminish side effects, and Novartis, Sanofi-Aventis, and Teva and lecture fees from Bayer,
                                                                                                                         improve compliance.32-34 This study showed that Biogen-Dompé, Novartis, Merck Serono, Sanofi-Aventis, and
   Hypertension                                             21 (5.0)             16 (3.7)                 8 (1.9)                                                             Teva; Dr. Hartung, receiving consulting and lecture fees from
                                                                                                                         once-daily oral fingolimod had superior efficacy Bayer Schering, Biogen Idec, Merck Serono, and Teva, consulting
Abnormal laboratory value                                                                                                to interferon beta-1a administered by weekly in- fees from Novartis, and grant support from Biogen Idec and
   Alanine aminotransferase increased                       24 (5.7)             28 (6.5)                 8 (1.9)        tramuscular injection. Fingolimod was associated Bayer Schering; Dr. Khatri, receiving consulting fees from Bayer,
   Lymphocytopenia                                           4 (1.0)                 1 (0.2)              0                                                                N Biogen Idec, Medtronics, Pfizer, Serono; Dr.Serono and lecture
                                                                                                                         with clearly identified adverse events, some of Engl Bayer, Biogen 2010;362:387-401.
                                                                                                                                                                              fees from J Med Idec, and
                                                                                                                                                                                                                Teva, and
                                                                                                                                                                                                                            Montalban, receiv-
Mt Sinai J Med 78:176–191, 2011.


• 亜急性, 慢性症状ならば, 非薬物治療から考慮.

  • リハビリ, Psychosocial supportを優先.

  • ICAP methodというものがよく使用される;
     Identification of symptoms; 症状を検出
     Causation of symptoms; 気づかせる
     Alleviation of symptoms; 症状を緩和する.
     Prevention of complications; 予防する という方法論.

  • 薬物治療ならば対症療法となる.
180                                                                          A. B. BEN-ZACHARIA: THERAPEUTICS FOR MS SYMPTOMS
                                                                                                    Mt Sinai J Med 78:176–191, 2011.

      Table 3.     Fatigue   Medications.37 – 40
                                                                       怠感はMSの2/3で認める症状.
      Medication                          Mechanism of Action            Dose                         Side Effects
      Amantadine (Symmetrel)              Potentiates catecholaminer-    100–200 mg                   Hallucinations, confusion,
                                            gic/dopaminergic                                            insomnia, and dizziness
                                            transmission
      Fluoxetine (Prozac)                 SSRI; increases serotonin in   Initial dose 10–20 mg; may   Insomnia, anxiety,
                                            the brain and has an           increase to higher           headache, flu-like
                                            effect on energy levels        dosage based on              symptoms, GI symptoms,
                                                                           individual assessment        dry mouth, somnolence,
                                                                                                        weight loss or gain,
                                                                                                        decrease in libido
      Modafinil (Provigil)                 Activates the                  Initial dose 100–200 mg;     Cardiac contraindications
                                            hypothalamus; increases        may increase up to           and reduction of BCP
                                            release of                     400 mg daily                 efficacy. Insomnia,
                                            norepinephrine and                                          anxiety, irritability,
                                            dopamine                                                    nausea, diarrhea,
                                                                                                        palpitations. SAE:
                                                                                                        Stevens-Johnson
                                                                                                        syndrome.
      Armodafinil (Nuvigil)                A single-isomer of             50–250 mg                    Headache, nausea,
                                             modafinil binds to the                                      insomnia, dizziness.
                                             dopamine transporter                                       Studies do not show
                                             and inhibits dopamine                                      clinical advantages
                                             reuptake                                                   versus Provigil.
      Methylphenidate (Ritalin)           Increases dopamine and         5–10 mg                      Angina, arrhythmias,
                                             norepinephrine in the                                      palpitations, tachycardia,
                                             brain through reuptake                                     BP/HR changes,
                                             inhibition of monoamine                                    diaphoresis, dizziness,
                                             transporters                                               dry mouth
      Amphetamine and                     Stimulant of CNS, as above     Initial dose 5–40 mg in      Anorexia, abdominal pain,
       dextroamphetamine                                                   divided doses; may           insomnia, nervousness,
       composite (Adderall,                                                increase up to 60 mg. XR     emotional lability
       Adderall XR)                                                        formulation: 20 mg once
                                                                           daily.

      Abbreviations: BCP, birth control pills; BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HR, heart
      rate; SAE, serious adverse event; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
Mt Sinai J Med 78:176–191, 2011.

Table 4.     Antispasticity Oral and Injectable Medications.11,37 – 39

Medication                     Mechanism of Action               Dose                                Side Effects
Baclofen (Lioresal)            GABA agonist                      Initial dose 5–10 mg 2–3×           Fatigue, somnolence,
                                                                   daily with gradual                  weakness, dizziness, GI
                                                                   titration                           symptoms, bladder
                                                                                                       dysfunction
Tizanidine (Zanaflex)           Centrally acting                  Initial dose 2–4 mg at              Dry mouth, sedation,
                                 α2-adrenergic agonist             bedtime; titrate gradually          dizziness, orthostatic
                                                                   up to 36 mg/day                     hypotension, edema,
                                                                                                       drug-induced hepatitis
Gabapentin                     A GABA analogue                   Initial dose 100–300 mg             Dizziness, drowsiness,
  (Neurontin)                                                      1–2× daily; increase                peripheral edema
                                                                   gradually
Benzodiazepines                Enhances GABA with                Diazepam 5 mg+ as                   Drowsiness, cognitive
  diazepam (Valium)              anticonvulsant,                   needed; clonazepam                  impairment, agitation,
  and clonazepam                 muscle-relaxant, and              0.5–1 mg                            loss of libido
  (Klonopin)                     anxiolytic properties

Dantrolene (Dantrium)          Muscle relaxant that              Initial dose 25 mg daily;           CNS effects: speech and
                                abolishes                          increase to 3–4× daily              visual disturbances,
                                excitation-contraction             by 25 mg every few                  depression, confusion,
                                coupling in muscle cells           days, up to 100 mg                  hallucinations, headache,
                                                                                                       insomnia, seizures,
                                                                                                       nervousness
Botulinum toxin                Binds to presynaptic              Dose depends on site and            Weakness
  (Botox)                        calcium docking protein          severity of spasticity
                                 and inhibits the release
                                 of acetylcholine at the
                                 neuromuscular junction

Abbreviations: CNS, central nervous system; GABA, γ -aminobutyric acid; GI, gastrointestinal.
OUNT   SINAI JOURNAL OF MEDICINE                                                                                            18
                                                                                        Mt Sinai J Med 78:176–191, 2011.


 Table 5.     Neuropathic Pain Medications.37,38,41

 Medication                   Mechanism of Action             Dose                           Side Effects
 Gabapentin (Neurontin)       A GABA analogue                 Initial dose 100–300 mg        Dizziness, drowsiness,
                                                                1–2× daily; increase           peripheral edema
                                                                gradually based on
                                                                tolerance
 Pregabalin (Lyrica)          Increases level of neuronal     Initial dose 50 mg 3× daily;   Dizziness, ataxia,
                                GABA by increasing GAD          may be increased to            somnolence, confusion,
                                and modulates the influx         300 mg/day within 1 week       blurred vision, peripheral
                                of calcium                      based on efficacy and           edema
                                                                tolerability
 Carbamazepine                Reduces polysynaptic            Initial dose 200 mg twice      Diplopia, dizziness,
   (Tegretol)                   responses, blocks               daily; increase by up to       hyponatremia, blood
                                post-tetanic activity, and      200 mg/day weekly using        dyscrasias, lethargy;
                                may depress thalamic by         a twice-daily regimen of       contraindicated with
                                inhibition of voltage-gated     XR pills, or a 3–4×/day        MAOIs and bone marrow
                                sodium channels                 regimen of other               depression
                                                                formulations
 Topiramate (Topamax)         Blockage of                     25–400 mg/day                  Fatigue, somnolence,
                                voltage-dependent sodium                                       cognitive impairment
                                channels, an augmentation
                                of subtypes of the
                                GABA-A receptors
 Oxcarbazepine                Sodium channel inhibition       150–1200 mg/day                Dizziness, somnolence
  (Trileptal)

 Abbreviations: GABA, γ -aminobutyric acid; GAD, glutamic acid decarboxylase; MAOI, monoamine oxidase inhibitor;
 XR, extended release.

 dysfunction.15 Bladder dysfunction in MS ranges                combination     of   disorders.   Common       symptoms
Mt Sinai J Med 78:176–191, 2011.
Table 6.     Bladder Medications.38,42
Medication                   Mechanism of Action             Dose                               Side Effects
Oxybutynin (Ditropan)        Antimuscarinic properties       5 mg oral 3× daily; available      Anticholinergic side effects:
                               and spasmolytic action on       as transdermal patch and           dry mouth, constipation,
                               detrusor smooth muscle          XR tablets                         nausea, dysuria, abnormal
                               cells; blocks PSNS                                                 vision, dizziness,
                                                                                                  somnolence
Tolterodine (Detrol)         A competitive muscarinic        2–4 mg XR capsule                  As above
                               receptor antagonist; blocks     formulation
                               PSNS
Solifenacin (Vesicare)       A competitive muscarinic        Initial dose 5 mg once daily;      As above; contraindicated in
                               acetylcholine receptor          may increase to 10 mg              liver disease, closed-angle
                               antagonist; fewer CNS           daily                              glaucoma, urinary
                               effects because does not                                           retention, prolonged QT
                               cross BBB                                                          syndrome
Darifenacin (Enablex)        Muscarinic receptor blocker;    Initial dose of XR tablets is      As above; fewer CNS effects
                               blocks PSNS, allowing SNS       7.5 mg once daily; may be
                               to predominate                  increased to 15 mg once
                                                               daily
Trospium (Sanctura)          Muscarinic receptor blocker;    20 mg twice daily, taken           As above; fewer CNS effects
                               blocks PSNS, allowing SNS       ≥1 hour before meals or
                               to predominate                  on an empty stomach
Tamsulosine (Flomax)         α-1 antagonist; relaxes         Initial dose 0.4 mg once           Dizziness, unusual
                               bladder sphincter               daily; may be increased to         weakness, drowsiness,
                                                               0.8 mg daily                       insomnia, sexual issues,
                                                                                                  orthostatic hypotension
Betanechol (Urecholine)      Muscarinic receptor agonist;    25–50 mg 3–4× daily                Diaphoresis, dizziness,
                              stimulates PSNS                                                     lightheadedness,
                                                                                                  headache, flushing,
                                                                                                  increased salivation

Abbreviations: BBB, blood-brain barrier; CNS, central nervous system; PSNS, parasympathetic nervous system; SNS,
sympathetic nervous system; XR, extended release.
Mt Sinai J Med 78:176–191, 2011.


186                                                                      A. B. BEN-ZACHARIA: THERAPEUTICS FOR MS SYMPTOM


      Table 7.     Bowel Medications.37,39
      Medication                 Mechanism of Action             Dose                                Side Effects
      Sodium docusate            Holds water within the stool,   100–300 mg daily in divided         Abdominal cramps, gas,
        (Colace)                   providing a larger, softer      doses                               bloating, nausea, diarrhea
                                   stool
      Senna (Senokot)            Increases peristaltic           1–3 tablets daily, usually          As above
                                   movement of the intestine,      taken at night for a
                                   which forces stool out          morning bowel routine
      Bisacodyl (Dulcolax)       As above                        1–3 tablets daily, usually          As above
                                                                   taken at night for a
                                                                   morning bowel routine
      Psyllium (Metamucil)       Increases the bulk and          1 packet with a full glass of       As above
                                   volume of the stool,            water
                                   softens the stool and
                                   stimulates intestinal
                                   motility; effective when
                                   used daily and consumed
                                   with high fluid intake
      Glycerin suppository       Coats and softens the stool     1–2 suppositories as needed         As above
                                   by slowing intestinal
                                   absorption of fecal water


      present as erectile dysfunction, delayed ejaculation,          using sildenafil citrate (Viagra) in a crossover trial;
      and decreased libido, whereas in women, decreased              there was no significant improvement in sexual
      lubrication, reduced libido or anorgasmia, and                 symptoms.19 Lubricants and vibratory stimulation can
      altered vaginal sensation are very common. Primary,            be useful in women. In addition, the clitoral vacuum
Mt Sinai J Med 78:176–191, 2011.
Table 8.     Sexual Dysfunction   Medications.39

Medication                 Mechanism of Action            Dose                                Side Effects
Sildenafil (Viagra)         Increases PDE, therefore       50 mg as needed                     Abnormal vision, diarrhea,
                             increasing cGMP and            approximately 1 hour                flushing, headache, nasal
                             causing vasodilation           before sexual activity              congestion, urinary tract
                                                                                                infection; contraindicated
                                                                                                in history of cardiac
                                                                                                disease
Vardenafil (Levitra)        PDE5 inhibitor; increases      Initial dose 10 mg taken            As above
                             PDE, increases cGMP, and       30–60 minutes before
                             causes vasodilation            sexual activity. Dose may
                                                            be increased to maximum
                                                            of 20 mg based on efficacy
                                                            and side effects
Tadalafil (Cialis)          PDE5 inhibitor; increases      Initial dose 10 mg taken            As above
                             PDE, increases cGMP, and       prior to anticipated sexual
                             causes vasodilation            activity; may be increased
                                                            to 20 mg or decreased to
                                                            5 mg; effective to 36 hours
Intracavernous             A tri-mix combination          Start at a low dose and titrate     Penile pain, prolonged
  papaverine plus            therapy causing blood          up as needed                        erections, priapism,
  phentolamine and           vessels to expand,                                                 fibrosis
  prostaglandin E1           increasing blood flow
  penile injection           throughout the body and
  (Trimix or Bimix)          to the penis, facilitating
                             erection
Estrogens                  Hormonal replacement in        Vaginal preparation, topical        Vaginal bleeding,
                             females; increases vaginal     cream                               dysmenorrhea, vaginitis,
                             moisture  increases                                               endometrial hyperplasia,
                             clitoral sensitivity                                               cancer, breast changes,
                                                                                                cardiovascular effects,
                                                                                                dizziness, urinary issues,
                                                                                                anxiety

Abbreviations: cGMP, cyclic guanosine monophosphate; PDE, phosphodiesterase.
Table 9.     Depression Medications.43 – 45                                                     Mt Sinai J Med 78:176–191, 2011.
Medication                Mechanism of Action              Dose                             Side Effects
Fluoxetine (Prozac)       SSRI; increases serotonin and    20–80 mg/day                     Anxiety, insomnia, increased
                            alleviates mood                                                   appetite, tremors, GI
                                                                                              symptoms, headaches, rash,
                                                                                              and sexual dysfunction with
                                                                                              decreased libido
Sertraline (Zoloft)       As above                         Initial dose 50 mg once daily;   As above
                                                             may increase up to 200 mg
                                                             daily
Paroxetine (Paxil)        As above                         10–40 mg daily or up to          As above
                                                             60 mg if needed
Citalopram (Celexa)       As above                         Initial dose 20 mg once daily,   As above
                                                             generally with an increase
                                                             to 40 mg/day
Escitalopram              SNRI; increases serotonin and    10–20 mg daily as needed         As above
  (Lexapro)                 norepinephrine in the brain,
                            alleviating mood
Venlafaxine (Effexor)     As above                         Initial dose 75 mg/day in 2 or   As above
                                                             3 divided doses with food;
                                                             may be increased to 150 or
                                                             225 mg/day if needed
Duloxetine                As above                         Total of 40 mg/day (given as     As above
 (Cymbalta)                                                  20 mg twice daily) to
                                                             60 mg/day (given either
                                                             once daily or as 30 mg
                                                             twice daily)
Buproprion             Dopamine and                        100 mg 3×/day; XR form           Anxiety, insomnia, weight
  (Wellbutrin) or        norepinephrine reuptake             150 mg twice daily               loss; may lead to seizures at
  (Wellbutrin SR)        inhibitor; alleviates mood                                           higher dosages
Imipramine (Tofranil) TCA; increases serotonin and         Initial dose 75 mg/day,          Dry mouth, urinary retention,
                         norepinephrine in the brain         increased to 150 mg/day          constipation, BP/HR
                         by slowing the rate of                                               changes
                         reuptake
Amitriptyline (Elavil) As above                            Initial dose 75 mg/day in        As above
                                                             divided doses for a total of
                                                             150 mg/day
Nortriptyline             As above                         25 mg 3–4× daily; dosage         As above
  (Pamelor)                                                  should begin at a low level
                                                             and be increased as needed

Abbreviations: BP, blood pressure; GI, gastrointestinal; HR, heart rate; SNRI, serotonin norepinephrine reuptake inhibitor;
SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; XR, extended release.

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横断性脊髄炎 多発性硬化症について

  • 2. Transverse Myelopathy Ann Rheum Dis 2000;59:120-4, NEJM 2010;363:564-72  横断性脊髄症; 脊髄の全層に及ぶ障害 – 一般人口では1.34-8/millionと稀な疾患. – 全年齢に生じるが, 60%は小児. ピークは2峰性で, 10-19yr, 30-39yr. – 急速(24-72hr)に進行する運動, 感覚, 自律神経障害が特徴 対麻痺(運動, 感覚), 膀胱直腸障害. 精神症状(抑うつ)など. 腰痛, 痙攣, 視神経障害の合併もあり. – 合併しやすい疾患としては, 多発性硬化症, Viral Infection(HSV, Influenza, EBV) 予防接種(Smallpox, Influenza), 中毒(Baclofen, PC, 鉛). 15-30%は特発性 – 不明だが血管炎, 動脈閉塞によるNecrosisの機序が疑わしい
  • 3. Ann Rheum Dis 2000;59:120-4, NEJM 2010;363:564-72 – SLEとTransverse myelopathyの合併は稀であり, 1-2%程度 SLEで神経精神症状を来すのは75%程度 (抗リン脂質抗体陽性が64%とTM合併例に多い傾向) – 33%で前駆感染症の病歴を認める. 特に若年で多い傾向. British Journal of Hospital Medicine 2011;72:264-269 • 横断性脊椎炎の診断Criteria 両側性(対称性 or 非対称性)の運動, 感覚, 自律神経の中枢性障害 感覚異常のLevelが明らか 発症から4hr~21dで進行し, Nadirを認める 脊髄の炎症所見; CSF細胞数増加, IgG index上昇, MRIにて造影効果認める脊髄病変 圧迫, 放射線後, 悪性腫瘍, 血管由来の原因を除外 • IgG index = (CSF IgG/serum IgG) / (CSF Alb/serum Alb) • 診断に重要なのはMRIによる圧迫病変, 非炎症性疾患, 悪性腫瘍の除外と, MSの評価. NMO-IgGの評価.
  • 6. TMにてチェックすべき項目 • 自己免疫疾患ではSLE, Sjogren症候群で合併 他にはサルコイドーシス, 感染症, 傍腫瘍症候群, 変性疾患など. clinical pr actice N Engl J Med 2010;363:564­72. Table 2. Concise Differential Diagnosis and Diagnostic Testing for Transverse Myelitis.* Possible Cause Diagnostic Tests Infection Blood serologic studies; CSF culture, serologic studies, and PCR; chest radiography and other imaging as indicated Systemic autoimmune or inflammatory disease Clinical examination; serologic studies; chest and joint radiography; other tests or imaging as indicated by history and examination Paraneoplastic cause Chest radiography, computed tomography, or positron-emission tomography; comprehensive serum and CSF paraneoplastic antibody panel Acquired CNS demyelinating disease (multiple Brain MRI with gadolinium enhancement; CSF examination for cell count and differ- sclerosis, neuromyelitis optica) ential count, oligoclonal bands, and IgG index; tests of visual evoked potentials; serum NMO-IgG testing Postinfectious or postvaccination cause History taking that reveals clear, recent history of infection or vaccination; serologic confirmation of recent infection; exclusion of other causes * CNS denotes central nervous system, CSF cerebrospinal fluid, NMO neuromyelitis optica, and PCR polymerase chain reaction.
  • 7. corticosteroids, so they are no longer recommended. flexia. Multiple sclerosis typically is monosymptomatic Because of their ease of administration and wide avail- ability, intravenous immunoglobulins are frequently Table 1. Possible infective agents responsible for • TMの原因となり得る疾患 the preferred treatment. Plasmapheresis may cause acute transverse myelitis hypotension and is contraindicated in patients with underlying cardiac comorbidities (Van Koningsveld Bacterial infections Syphilis and Van Doorn, 2005). Abscess Rehabilitation Mycoplasma Acute phase rehabilitation should include an individual- Lyme disease ized programme of gentle strengthening, involving iso- Viral infections Encephalomyelitis metric, isotonic, isokinetic, and manual and progressive resistive exercises. Rehabilitation should emphasize prop- Poliovirus er limb positioning, posture and orthotics as well as Herpes zoster nutrition. Herpes virus B Rabies Prognosis The majority of patients will recover within weeks, but Human immunodeficiency virus 30% will still have weakness after 3 years and 3% will Autoimmune Systemic lupus erythematosus relapse. The overall mortality rate is around 3–4% (El Sjögren’s syndrome Mhandi et al, 2007). Sarcoidosis Acute transverse myelitis Vasculitis Epidemiology Vaccinations Bacillus Calmette–Guérin The disease has two peak incidences: between the ages Smallpox of 10–19 years, then again between the ages of 30–39 years. There have been few population-based Polio studies of acute transverse myelitis and there appears to Other Parasitic infection be no real link with any identifiable patient characteris- Fungal infection tics. There is no significant seasonal or annual fluctua- Acute multiple sclerosis tion in frequency. British Journal of Hospital Medicine 2011;72:264-269
  • 8. Case Review Ann Rheum Dis 2000;59:120-4  600名のSLE患者中, 14名にTM(+) (2.3%) – 14名 + 91例のCase Reportを合わせて評価 – TMはSLEの初発症状として出現することもあれば(39%), 発症~5年以内に出現することも多い(42%). (2/14で発症 >10yrで発症している, 11yr, 21yr)  MRIにて病変を認めるレベルはT5-T8が最も多い – 発症数日で上行性に感覚障害が進行. – 54%がTMに矛盾しない所見を示し, 70%が何らかな異常所見を示す  CSF所見ではWBC, Protの軽度上昇を示す  補体は正常 ~ 軽度低下
  • 9. Case Review Ann Rheum Dis 2000;59:120-4  完全寛解を示すのは22%程度 – 64%が不変, 14%が一部寛解を示す – 治療はステロイドパルス療法(MP 1g/d), Cyclophosphamide(1g/m2), Plasmapheresisなど報告あり  補足; SLEに合併する多発単神経炎では, – 上行性の感覚障害, 左右非対称の対麻痺を来す. SLE, 他の血管炎症候群による血管炎が原因とされ, Transverse Myelopathyと酷似する病態. – 末梢神経伝導速度による評価で鑑別できるかもしれないが, 大量ステロイド, Cyclophosphamideにて治療するため, 対応は変わらない. 迅速な治療が予後にかかわる.
  • 10. TMの治療 NEJM 2010;363:564-72 • ステロイド投与にて50-70%が反応を示す • 3-5dのステロイドパルスが多く行われる. • ステロイドに反応を示さない例では血漿交換がRescueとして行わ れる • 脱髄性疾患を合併している例では長期の免疫抑制療法が必要.  → 再発予防効果が認められる.(Cyclophosphamide) • 他には対症療法; 呼吸抑制, 痛, 筋力低下, 感覚低下, 脊髄性ショック, 膀胱直腸障害, 精神症状への対応が必要
  • 11. TM患者の長期フォロー Arch Neurol 2012;69:357-362 • Acute partial TMと診断された85名を104.8(29.8)moフォロー Table 1. Clinical Data on Presentation of Patients With Multiple Sclerosis and Patients With Undetermined Etiology Sex, No. Patients, No. (%) Age, Mean, Motor Sensory Sphincter Acute Subacute Group (Range), y Male Female Symptoms Symptoms Symptoms Onset Onset MS (n = 53) 34.8 (17-54) 14 39 21 (40) 51 (96) 7 (13) 8 (15) a 45 (85) a Undetermined 38.6 (16-76) 13 16 10 (34) 29 (100) 3 (10) 10 (34) 19 (66) (n = 29) Combined (n = 82) 36.7 (16-76) 27 55 31 (38) 80 (98) 20 (24) 18 (22) 64 (78) Abbreviation: MS, multiple sclerosis. aP= .03 (comparison between the MS and undetermined groups determined by use of the ␹2 test). Table 2. Data of Spinal Cord Magnetic Resonance Imaging on Presentation Patients, a No./Total No. (%) Lesions, Mean Sagittal Plane Axial Plane Mean Vertebral (Range), Level, Postero- Centro- Gadolinium Group No. No. Cervical Dorsal Lumbar Anterior Lateral Posterior Central lateral lateral Enhancement MS (n = 53) 1.23 (0-6) 1.51 27/52 (52) 25/52 (48) 5/52 (10) 1/39 (3) 19/39 (49) b 19/39 (49) 7/39 (18) c 38/39 (97) d 26/39 (67) 26/47 (55) c Undetermined 1.21 (0-5) 1.33 14/29 (48) 14/29 (48) 2/29 (7) 0/26 (0) 5/26 (19) 14/26 (54) 11/26 (42) 19/26 (73) 16/26 (62) 9/26 (35) (n = 29) Combined 1.22 (0-6) 1.42 41/81 (51) 39/81 (48) 7/81 (9) 1/65 (2) 24/65 (37) 33/65 (51) 18/65 (28) 57/65 (88) 42/65 (65) 35/73 (48) (n = 82) Abbreviation: MS, multiple sclerosis. a Comparisons between the MS and undetermined groups determined by use of the ␹2 test. b P = .03. c P = .02. d P = .011.
  • 12. Arch Neurol 2012;69:357-362 • フォロー中に62%がMSと診断され, 感染後脊髄炎, Sjogren症候群, NMOと診断されたのが各1%. 34%は原因不明のAPTMのまま経過. • 後々MSと診断される例は, CSF oligoclonal bandsと MRIにて脳病変を認める例が多い. APTM MS OR Oligoclonal bands 38% 92% 15.76[2.95-84.24] 脳MRI所見 27% 87% 7.74[2.42-24.74] Table 3. Results of Paraclinical Examination at Presentation Patients, No./Total No. Brain MRI Results CSF Analysis Fulfilling Protein Level, Cell Count, No Ն1 Barkhof et Mean (Range), Mean (Range), Presence Abnormal Group Lesions Lesions al15 criteria g/dL cells/mm3 of OCBs VEPs MS 7/52 (13) a 45/52 (87) b 28/52 (54) c 4.5 (1.6-9.2) 13.5 (0-87) 43/47 (91) d 20/46 (43) e Undetermined 19/26 (73) 7/26 (27) 0/26 (0) 5.2 (1.9-14.3) 9.38 (0-133) 10/26 (38) 1/26 (4) Combined 26/78 (33) 52/78 (67) 28/78 (36) 4.8 (1.6-14.3) 11.42 (0-133) 53/73 (73) 21/72 (29) Abbreviations: CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis; OCBs, oligoclonal bands; VEPs, visual evoked potentials. SI conversion factor: To convert protein to grams per liter, multiply by 10.0. a P = 5 ϫ 10−7. b P = 5.43 ϫ 10−7. c P = 9 ϫ 10−6. d P = 4 ϫ 10−6. e P = .001.
  • 13. Multiple Sclerosis Neurology" 2012;79 (Suppl 2):S1–S15 • CNSの炎症性, 脱髄性変化を来す慢性疾患. • 主に脱髄とAxonの損傷が認められる. 障害部位はCNS全般. 白質, 小脳, 脳幹, 脊髄, 視神経. • 症状は様々で, 単独の症状∼複合症状. 認知障害, 怠感, 運動障害, 歩行障害, 視覚障害, 感覚障害, 膀胱直腸障害, 神経性 痛など. • 病状の進行形式も様々. 急速に増悪, 寛解を繰り返し, 徐々に障害を残す (歩行障害など.) • MSの平均年齢は30歳. 70%が20-40歳で発症する. • 男女比は1:3と女性に多い.
  • 14. Neurology" 2012;79 (Suppl 2):S1–S15 • MSのパターン; • Clinically isolated syndrome(CIS); MS様症状の初回発作. (視神経炎, 脊髄炎, 脳幹症状). 空間的, 時間的解離の要素は無い. • Relapsin-remitting MS(RRMS); 増悪と寛解を繰り返す. 寛解期には症状は完全に改善する. MSの80-85%が初期にはRRMS • Primary progressive MS(PPMS); 初回発作から徐々に増悪する経過. 軽快は認めるが, 完全には良くならず, 全体的に増悪する経過. MSの10-15%が当てはまる. • Secondary progressive MS(SPMS); RRMSを経て, 増悪に移行する 経過を示す. RRMSの大半がこのパターンに移行する. • Progressive relapsing MS; 寛解, 増悪を繰り返しながら, 徐々に増悪するタイプ. PPMSとの区別は難しい.
  • 15. Neurology" 2012;79 (Suppl 2):S1–S15 • 他のMS suptype • Benign MS; RRMSで10年以上EDSS score<3.0を満たすもの (Expanded Disability Status Scale)  • Single-attack progressive MS; PPMSのSubtype • Malignant or fulminant MS; 急速進行性のMS. 数ヶ月で重度の障害を来す. • Transitional MS; RRMSとSPMSの移行期.
  • 16. MSの画像所見 Neurology" 2012;79 (Suppl 2):S1–S15 • 白質, 小脳, 脳幹, 脊髄病変がDIS, DITで認める. • DIS; Dissemination in space; 連続性のない病変をMRIにて確認.  よく使用されるのはMcDonald criteria(次スライド) • DIT; Dissemination in time; フォローMRIにて  T2 high, Ga造影病変が新規に出現していることで定義. • 上記+典型的なMRI所見を認めればMSと診断する事が多い.
  • 17. Articles MSの画像所見 Lancet Neurol 2011; 10: 1065–73 • 各診断Criteriaの感度, 特異度 (284名の疑い患者の3.9yフォロー. 内20%が後にMS. ) ≥1 periventricular lesion and 2005 McDonald DIS*2 Paediatric MS†5 Paediatric MS-ADEM‡6 KIDMUS§7 ≥1 T1-hypointense lesions Sensitivity 48/57 (84%) 32/57 (56%) 42/57 (74%) 54/57 (95%) 23/57 (40%) Specificity 212/227 (93%) 164/227 (72%) 154/227 (68%) 205/227 (90%) 222/227 (98%) Positive predictive value 48/63 (76%) 32/95 (34%) 42/115 (37%) 54/76 (71%) 23/28 (82%) Negative predictive value 212/221 (96%) 164/189 (87%) 154/169 (91%) 205/208 (99%) 222/256 (87%) Youden’s J 0·77 0·28 0·42 0·85 0·38 Data are number (%). DIS=dissemination in space. MS=multiple sclerosis. ADEM=acute disseminated encephalomyelitis. KIDMUS=kids with multiple sclerosis. *Three of the following lesion patterns: nine or McDonald DIS Paediatric MS Paediatric MS-ADEM KIDMUS more T2 lesions or one or more gadolinium lesion, three or more periventricular lesions, one or more juxtacortical lesion, or one or more infratentorial lesion. †Two of the following lesion patterns: five or more T2 lesions, two or more periventricular lesions, or one or more brainstem lesion. ‡Two of the following lesion patterns: two or more periventricular lesions, one or more T1-hypointense lesions, absence of diffuse 以下の3つ以上を満たす 以下の2つ以上を満たす 以下の2つ以上を満たす 以下の2つ以上を満たす bilateral pattern. §Two of the following lesion patterns: Dawson fingers (lesions perpendicular to the long axis of the corpus callosum) and one or more well defined lesion. Table 4: Comparison of published MRI criteria with proposed predictive parameters for diagnosis of multiple sclerosis ≥9箇所のT2病変を認める ≥5箇所のT2病変 ≥2箇所の脳室周囲病変 Dawson fingers* ≥1箇所のgadoliium病変 ≥2箇所の脳室周囲病変 ≥1箇所のT1で低信号病変 ≥1箇所の明瞭な病変 ≥3箇所の脳室周囲病変 unchanged when contrast-enhancement was 両側性パターン無しobtained more than 12 months after remained ≥1箇所の脳幹病変 びまん性, basis of MRI scans added. After adjustment for onset age and sex, contrast- onset. The diagnostic usefulness of one or more ≥1箇所のJuxtacortical lesion lesions were not significantly associated with periventricular lesions and one or more T1-hypointense enhancing MS diagnosis. * Dawson fingers; 脳梁の垂直方向性の病変 lesions in the entire cohort (table 4) did not differ from the ≥1箇所のテント下病変 The presence of both one or more periventricular lesions performance of these parameters in the 108 participants and one or more T1-hypointense lesions at baseline was who had annual MRIs (sensitivity 83%, specificity 92%, strongly predictive of MS (hazard ratio 34·27, 95% CI PPV 68%, NPV 97%) or in the 176 children who did not 16·69–70·38, figure 2). 48 of 57 children subsequently have annual MRI scans (sensitivity 85%, specificity 94%,
  • 18. Neurology" 2012;79 (Suppl 2):S1–S15 Table 1 Summary of 2005 and 2010 McDonald criteriaa Additional data needed for MS diagnosis Clinical presentation 2005 2010 ‡2 attacks; objective clinical evidence None None of ‡2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack ‡2 attacks; objective clinical evidence Dissemination in space demonstrated by: Dissemination in space according to new definition: of 1 lesion MRI (Barkhof-Tintoré criteria) or $1 lesion in 2 of 4 characteristic areas $2 MRI-detected lesions consistent with (periventricular, juxtacortical, infratentorial, MS plus positive CSF or or spinal cord) or A further clinical attack implicating a different A further clinical attack implicating a different CNS site CNS site 1 attack; objective clinical evidence Dissemination in time demonstrated by: Dissemination in time according to new definition: of ‡2 lesions MRI (new T2 lesion after baseline scan 30 d New T2 and/or Gd-enhancing lesion at follow-up or after initial event or Gd-enhancing 3 mo Simultaneous presence of enhancing and nonenhancing after event) or lesions or A further clinical attack A further clinical attack 1 attack; objective clinical evidence Dissemination in space and time as above Dissemination in space and time according to new definitions of 1 lesion (CIS) Insidious neurologic progression 1 y of disease progression plus 2 of: Same as in 2005 criteria, but use new DIS definitions suggestive of MS (PPMS) Positive brain MRI Positive spinal cord MRI Positive CSF Abbreviations: CIS 5 clinically isolated syndrome; DIS 5 dissemination in space; Gd 5 gadolinium; MS 5 multiple sclerosis; PPMS 5 primary progressive MS. a Adapted from Polman et al., 2011,15 with permission. CIS and MS has been moving toward earlier and CLINICAL IMPLICATIONS OF THE 2010 UPDATE earlier diagnosis of MS. Widening the window. One of the most important
  • 19. there is a historical suggestion of an earlier relapse? standard in this population. Neurology 2012;79 (Suppl 2):S1–S15 Figure Recommended algorithm for diagnosis of inflammatory demyelinating disease ADEM 5 acute disseminated encephalomyelitis; CIS 5 clinically isolated syndrome; DIS 5 dissemination in space; DIT 5 dissemination in time; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica. Adapted from Miller et al.32 (by permission of Sage Publications, © 2008). Neurology 79 (Suppl 2) December 4, 2012
  • 20. MSの治療 Mt Sinai J Med 78:176–191, 2011. • MSの治療は疾患自体に対する治療(DMTs)と対症療法がある MOUNT SINAI JOURNAL OF MEDICINE (Disease-modifying therapeutics;DMTs)  Table 1. Primary, Secondary, and Tertiary Symptoms in Multiple Sclerosis. • 症状も急性症状, 亜急性(6mo), Symptom Primary Secondary Tertiary 慢性(6mo)があり, Weakness X X また, 脱髄自体による症状, Sensory loss Vision loss X X その症状に随伴するものと, Diplopia Impaired balance X X X 様々な現れ方がある. Incoordination Sexual dysfunction X X X X Bladder symptoms X X Bowel issues X X Cognitive dysfunction X X X Fatigue X X X Depression X X X Anxiety X X X Social isolation X X INO/nystagmus X Contractures X Vertigo X Speech issues X Swallow issues X Pain X X X Spasticity X X Abbreviations: INO, internuclear ophthalmoplegia.
  • 21. Mt Sinai J Med 78:176–191, 2011. • 急性期治療はステロイド. • 症状に応じてmPSLパルス, PSL 1mg/kg/dが選択される. 効果不十分の場合は血漿交換も考慮する. • ステロイド投与経路はIV, POどちらも効果は同等. • MSの寛解期, 安定期には増悪予防が重要となる. その為の薬剤がDMTsであり, 現在最も研究が盛んな分野.
  • 22. 62 DMTs J. DERWENSKUS: DISEASE-MODIFYING TREATMENT OF MULTIPLE SCLEROS MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011 Table 1. FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis. Medication Dose Route Frequency Approved in US Pregnancy Category Fingolimod (Gilenya) 0.5 mg Oral Daily 2010 C Glatiramer acetate (Copaxone) 20 mg SC Daily 1996 B IFNβ-1a (Avonex) 30 µg IM 1× weekly 1996 C IFNβ-1b (Betaseron) 0.25 mg SC Every other day 1993 C IFNβ-1b (Extavia) 0.25 mg SC Every other day 2009 C IFNβ-1a (Rebif) 22, 44 µg SC 3× weekly 2002 C Mitoxantrone (Novantrone) 12 mg/m2 IV Every 3 months 2000 D Natalizumab (Tysabri) 300 mg IV Monthly 2004/2006 C Abbreviations: IM, intramuscular; IV, intravenous; SC, subcutaneous; US, United States. • DMTsはMSの増悪を予防する薬剤. FDAでは8つが承認. likely will change as more effective therapies become in MS. However, more recently the effect of IFN-β on available. T helper 17 has been discovered to also be playing a role.2 The advent of disease-modifying therapy has changed the focus of managing multiple sclerosis Interferon Pivotal Trials from the treatment of acute The first pivotal study leading to FDA approval of exacerbations to the prevention IFN-β in relapsing-remitting MS (RRMS) was reported by the IFNB Multiple Sclerosis Study Group.3 This of new disease activity. There
  • 23. exacerbations to the prevention IFN-β in relapsing-remitting MS (RRMS) was reported MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011 by the IFNB Multiple Sclerosis Study Group.3 This of new disease activity. There was a randomized, double-blind, placebo-controlled are currently 8 FDA-approved study of 372 patients with clinically definite MS. • β-Interferon;this purpose therapies for 機序は未だ詳しくは不明だが, Patients were randomized to either placebo or 1.6 or 8  MS予防効果が認められている.2IFN-β-1b third-year double-blindevery other was and numerous others in clinical MIU for years. A given as a SC injection extension day trials. included as part of this study. There was a significant • T cellがCNSへ移行するのを予防することで予防する. rate (ARR) of reduction in the annualized relapse almost 34% in the higher-dose IFN-β-1b group, which BETA-INTERFERONS was the primary outcome measure (Figure 1). There • RRMS 372名のDB-RCTでは, 高用量IFN-β-1b群で有意な 1.17 attacks were 1.27 attacks per year for placebo, per year for the 1.6 MIU group, and 0.84 attacks 再燃頻度の低下が認められた. per year34%the 8 MIU group (placebo versus 8 Beta-interferon (IFN-β) was the first class of therapy ARR for approved to treat MS. IFN-β-1b (Betaseron) given subcutaneously (SC) every other 1.6MIU 1.17 vs 8MIU 0.84回/yr) (Placebo 1.27 vs day was approved by the FDA in 1993. Since then, 3 additional IFN-β have been approved in the United States: IFN-β-1a • PRISMS trialでは, (Avonex), given as a weekly intramuscular (IM) injec- IFN-β-1a 22µg-44µg 3回/wkで tion, in 1996; IFN-β-1a (Rebif), given as a SC injection 3× weekly, in 2002; and IFN-β-1b (Extavia), given as 有意に再発率を低下. a SC injection every other day, in 2009. Although the exact mechanism of action is unknown, IFN-β drugs likely have multiple effects on the • IFNの副作用は, immune system.1 The effects in the periph- Flu-like症状, 75%で認められる ery include inhibition of antigen presentation, and at the blood-brain barrier there is down-regulation 75%が3moで減弱, production of of adhesion molecules and decreased 消失. matrix metalloproteinases. This limits the entry of T cells into the central nervous system (CNS). Clas- sically the emphasis has been on IFN-β causing a Fig 1. Kaplan-Meier analysis showing the probability of remaining exacerbation-free in the first 2 years of the study shift from T helper 1 to T helper 2 cells, creating an comparing 2 different doses of IFN-β to placebo. anti-inflammatory milieu as an important mechanism
  • 24. MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011 • Glatiramer acetate; 未承認 • RRMS 251名のRCTでは, 2年後の再年率は有意に低下. Glatiramer 20mg/d SC vs Placebo; (1.19 vs 1.68, p=0.007). • 副作用は少なく, 投与部位の発赤程度. • Mitoxantrone; ノバントロン® • AML, 前立腺癌に対する抗癌剤. MOUNT SINAI JOURNAL OF MEDICINE B-cellの抑制, Mφによる脱髄を抑制する. • MIMS trial; PPMS 194名のDB-RCT (Placebo vs MIT 5, 12mg/m2 3mo) • 2年継続し, 症状, 再燃を評価. 12mg/m2群で有意に頻度低下.  @36mでも効果持続しており,  薬剤中止後も効果が期待できる. • MITの極量は140mg/m2 (積算) Fig 4. Time to first treated relapse.
  • 25. MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011 • Natalizumab; 未承認, α4 β1 integrinのα4 subunitを阻害. • CNSへのLyの移行を阻害する作用を示す. • AFFIRM study; RRMS 942名のRCT.  natalizumab 300mg q4wk vs Placeboで2y継続. • 開始後1年間での再燃率は0.26 vs 0.81, p0.001と 有意にnatalizumabで再燃リスクが軽減. • SENTINEL study; RRMSでIFN-β-1a 30µg/wk投与下でも  再燃を認めた1171名のRCT.  natalizumab追加群 vs IFN継続群で再燃率を比較. • 再燃率は0.38 vs 0.82と有意で併用群で低下を認めた. • Natalixumabではmultifocal leukoencephalopahtyのリスクがあり,  発症率は1/1000との報告があり, 注意が必要.
  • 26. phase III clinical trials. The FTY720 Research Evaluat- MOUNT SINAI JOURNAL OF MEDICINE 78:161–175, 2011 ing Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trial was a randomized, double-blind, placebo-controlled study of 1272 patients comparing • Fingolimod; ジレニア, イムセラ ® 2 doses of fingolimod (0.5 mg or 1.25 mg) versus placebo taken once daily for 24 months.37 Included subjects were ages 18–55 years and had RRMS. • RRMSに対する経口投与可能な薬剤. Patients were excluded if they had been treated with steroids within 30 days of randomization, had an Sphingosine-1-phosphate-Rの調節剤であり, active infection, or had history of macular edema, diabetes mellitus, immune suppression, or clinically リンパ節からリンパ球が放出されるのを抑制する. significant systemic disease. Standard DMT such as IFN-β or glatiramer acetate was stopped ≥3 months   リンパ球が低下し, CNSでの脱髄が抑制される機序. J. DERWENSKUS: DISEASE-MODIFYING TREATMENT OF MULTIPLE SCLEROSIS before randomization. Patients had neurologic exam- inations performed every 3 months, and MRI scans he approval of fingolimod was based on 2were done at 6, 12, and 24 months. The study met • FREEDOMS trial; RRMS患者1272名のDB-RCT. III clinical trials. The FTY720 Research Evaluat- outcome measure with a reduction in the its primary fects of Daily Oral Therapy in Multiple Sclerosis0.18 in the 0.5-mg group and 0.16 in the ARR to  Fingolimod 0.5mg, 1.25mg vs Placebo, 24mo継続群で比較. DOMS) trial was a randomized, double-blind, group, respectively, compared with 0.40 in 1.25-mg bo-controlled study of 1272 patients comparing the placebo group. This corresponded to a relative es of fingolimod (0.5 mg or 1.25 mg) versus of 54% and 60% in the ARR (P 0.001). reduction • 0.5mg, 1.25mg群はPlaceboと比較して再燃率, 増悪が少ない. bo taken once daily for 24 months.37 Other secondary outcomes also favored fingolimod. cts were ages 18–55 years and had RRMS. Included Dose間では有意差無く, 0.5mg/dで十分. ts were excluded if they had been treated with The FREEDOMS trial was a dsDwithin-MODIFYING Trandomization, ULTIPLE SCLEROSIS : ISEASE 30 days of REATMENT OF M had an randomized, double-blind, infection, or had history of macular edema, es mellitus, immune suppression, or clinically placebo-controlled study of 1272 cant systemic disease. Standard DMT such as patients comparing 2 doses of or glatiramer acetate was stopped ≥3 months e randomization. Patients had neurologic exam- fingolimod (0.5 mg or 1.25 mg) ns performed every 3 months, and MRI scans done at 6, 12, and 24 months. The study versus placebo taken once daily met mary outcome measure with a reduction in the 24 months. The study showed a for o 0.18 in the 0.5-mg group and 0.16 in the reduction in the ARR to 0.18 in mg group, respectively, compared with 0.40 in acebo group. This corresponded to a relative 0.5-mg group and 0.16 in the the tion of 54% and 60% in the ARR (P 0.001). 1.25-mg group, respectively, secondary outcomes also favored fingolimod. compared with 0.40 in the placebo The FREEDOMS trial was a
  • 27. N Engl J Med 2010;362:387-401. • FREEDOMS study; 18-55歳のRRMS 1272名のDB-RCT. • EDSS score 0-5.5で, 過去1年以内に1回以上,  過去2年以内に2回以上の再燃を繰り返している患者群. • Fingolimod 0.5mg vs 1.25mg vs Placeboに割り付け, 24m継続し, 各群の再燃率を比較. • アウトカム; 治療を24m継続できたのは81.2%.  中断率は0.5mg群で18.8%, 1.25mg群で30.5%, Placeboで27.5%. Outcome 1.25mg 0.5mg Placebo 1.25 vs P 0.5 vs P 再年率/y 0.16[0.13-0.19] 0.18[0.15-0.22] 0.40[0.34-0.47] P0.001 P0.001 再燃(-)率 @24m 74.7%[70.4-78.9] 70.4%[66.0-74.8] 45.6%[40.7-50.6] HR0.38[0.30-0.48] HR0.48[0.39-0.61] 障害の進行(-)率 83.4%[79.7-87.1] 82.3%[78.6-86.1] 75.9%[71.7-80.2] HR0.68[0.50-0.93] HR0.70[0.52-0.96] Ga造影(+) 数@24m 0.2±1.1 0.2±0.8 1.1±2.4 0.001 0.001 Ga造影(+)病変(-)率@24m 89.8% 89.7% 65.1% 0.001 0.001 T2病変 増悪, 新規(-) @24m 51.9% 50.5% 21.2% 0.001 0.001 • Fingolimod群の方が有意に再年率, 新規病変の出現が軽減.  脳実質量の比較でも有意に低下が少なくなる.
  • 28. N Engl J Med 2010;362:402-15. • TRANSFORMS study; RRMS 1292名のDB-RCT. • Inclusion criteriaはFREEDOMS studyと同様. • Fingolimod 1.25mg vs 0.5mg vs INF-β-1a 30µg/wkに割り付け, 12mo継続し, 再年率を比較. • アウトカム; 治療を継続できたのは89%. Outcome 1.25mg 0.5mg IFN 1.25 vs IFN 0.5 vs IFN 再年率/y 0.20[0.16-0.26] 0.16[0.12-0.21] 0.33[0.26-0.42] 0.001 0.001 再燃(-) 率@12mo 79.8%[75.9-83.7] 82.6%[79.0-86.3] 69.3%[64.8-73.8] 0.001 0.001 T2病変増悪, 新規 (-) 48.0% 54.8% 45.7% 0.37 0.01 Ga造影病変増悪, 新規(-) 91.2% 90.1% 80.8% 0.001 0.001 • FingolimodはIFN-β-1aよりも再燃予防効果が高い.  また, 病変の出現, 増悪リスク, 神経機能増悪リスクも低い.
  • 29. Table 3. Adverse Events in the Safety Population, According to Study Group. Table 3. (Continued.) Event Fingolimod Placebo (N = 418) Event Fingolimod Placebo (N = 418) 1.25 mg (N = 429) 0.5 mg (N = 425) 1.25 mg (N = 429) 0.5 mg (N = 425) no. of patients (%) no. of patients (%) All events Psychiatric disorders At least one adverse event 404 (94.2) 401 (94.4) 387 (92.6) Depression 26 (6.1) 33 (7.8) 28 (6.7) Any adverse event leading to discontinuation of study 61 (14.2) 32 (7.5) 32 (7.7) Insomnia 16 (3.7) 21 (4.9) 25 (6.0) drug* Hypercholesterolemia 26 (6.1) 24 (5.6) 26 (6.2) Any serious adverse event 51 (11.9) 43 (10.1) 56 (13.4) Weight increase 14 (3.3) 14 (3.3) 22 (5.3) Death 1 (0.2) 0 2 (0.5) Vertigo 18 (4.2) 18 (4.2) 21 (5.0) Frequent or special-interest adverse events† Macular edema 7 (1.6) 0 0 Infections Serious adverse events¶ Upper respiratory tract infection 206 (48.0) 212 (49.9) 211 (50.5) Cardiovascular disorders Nasopharyngitis 112 (26.1) 115 (27.1) 115 (27.5) Sinusitis 27 (6.3) 28 (6.6) 19 (4.5) Bradycardia 3 (0.7) 4 (0.9) 1 (0.2) Pharyngitis 25 (5.8) 27 (6.4) 24 (5.7) Myocardial infarction 0 0 2 (0.5) Rhinitis 18 (4.2) 25 (5.9) 25 (6.0) Neoplasms Influenza virus infection 40 (9.3) 55 (12.9) 41 (9.8) Basal-cell carcinoma 1 (0.2) 4 (0.9) 3 (0.7) Lower respiratory tract or lung infection 49 (11.4) 41 (9.6) 25 (6.0) Breast cancer 1 (0.2) 0 3 (0.7) Bronchitis 39 (9.1) 34 (8.0) 15 (3.6) Malignant melanoma 1 (0.2) 0 1 (0.2) Pneumonia 8 (1.9) 4 (0.9) 3 (0.7) Bowen’s disease 1 (0.2) 0 0 Herpesvirus infection‡ 25 (5.8) 37 (8.7) 33 (7.9) Cervical carcinoma, stage 0 0 0 1 (0.2) Urinary tract infection 21 (4.9) 34 (8.0) 47 (11.2) Endometrial cancer 0 0 1 (0.2) Nervous system disorders Prostate cancer 0 0 1 (0.2) Headache 114 (26.6) 107 (25.2) 96 (23.0) Nervous system disorders Dizziness 30 (7.0) 31 (7.3) 23 (5.5) MS relapse 3 (0.7) 4 (0.9) 1 (0.2) Paresthesia 17 (4.0) 23 (5.4) 18 (4.3) Epilepsy 2 (0.5) 0 0 Abnormal laboratory liver-function test§ 80 (18.6) 67 (15.8) 21 (5.0) Headache 2 (0.5) 0 0 Fatigue 47 (11.0) 48 (11.3) 45 (10.8) General disorders Musculoskeletal disorders Chest pain 0 4 (0.9) 2 (0.5) Back pain 45 (10.5) 50 (11.8) 29 (6.9) Macular edema 3 (0.7) 0 0 Arthralgia 27 (6.3) 30 (7.1) 33 (7.9) Laboratory evaluation Pain in extremity 24 (5.6) 28 (6.6) 28 (6.7) Abnormal liver-function test 2 (0.5) 0 1 (0.2) Gastrointestinal disorders Lymphopenia 2 (0.5) 0 0 Diarrhea 40 (9.3) 50 (11.8) 31 (7.4) Depression 2 (0.5) 0 1 (0.2) Nausea 38 (8.9) 38 (8.9) 36 (8.6) Musculoskeletal disorders Respiratory disorders Back pain 0 2 (0.5) 1 (0.2) Cough 37 (8.6) 43 (10.1) 34 (8.1) Intervertebral disk protrusion 0 0 2 (0.5) Dyspnea 23 (5.4) 30 (7.1) 19 (4.5) Abortion 0 0 3 (0.7) Oropharyngeal pain 17 (4.0) 29 (6.8) 29 (6.9) Urinary tract infection 0 2 (0.5) 0 Blood and lymphatic system disorders Leukopenia 27 (6.3) 12 (2.8) 1 (0.2) * “Any adverse event leading to discontinuation of the study drug” includes events occurring in patients whose primary or secondary reason for discontinuing the study drug was an adverse event (including abnormal laboratory findings). Lymphopenia Cardiovascular disorders 23 (5.4) 15 (3.5) 2 (0.5) FREEDOMSの副作用; † “Frequent adverse events” includes those reported in 5% or more of patients in any group. ‡ The terms used to report herpesvirus infection included oral herpes, herpesvirus infection, herpes simplex virus infec- Hypertension 27 (6.3) 26 (6.1) 16 (3.8) tion, herpes zoster, genital herpes, and herpes dermatitis. Bradycardia, bradyarrhythmia, or sinus bradycardia Atrioventricular block 14 (3.3) 9 (2.1) 3 (0.7) 不整脈と黄斑浮腫のチェックは大事 § The terms used to report an abnormal laboratory liver-function test included increased levels of alanine aminotrans- ferase, aspartate aminotransferase, γ-glutamyltransferase, hepatic enzyme, and aminotransferases, and abnormal liver-function tests or γ-glutamyltransferase levels. First degree 5 (1.2) 2 (0.5) 2 (0.5) ¶ “Serious adverse events” includes those reported in two or more patients in any group or of special interest. “MS relapse” includes both events related to the worsening of multiple sclerosis (MS) and MS relapses. See the Second degree 1 (0.2) 0 1 (0.2) Supplementary Appendix for further details. N Engl J Med 2010;362:387-401.
  • 30. Table 3. Adverse Events and Serious Adverse Events (Safety Population).* Table 3. (Continued.) Interferon Beta-1a Interferon Beta-1a Event Fingolimod (N = 431) Event Fingolimod (N = 431) 1.25 mg (N = 420) 0.5 mg (N = 429) 1.25 mg (N = 420) 0.5 mg (N = 429) no. of patients (%) no. of patients (%) All adverse events Serious adverse events Any event 380 (90.5) 369 (86.0) 395 (91.6) Any serious event 45 (10.7) 30 (7.0) 25 (5.8) Any event leading to discontinuation of a study drug 42 (10.0) 24 (5.6) 16 (3.7) Death 2 (0.5)† 0 0 Most frequently reported adverse events Cardiovascular disorder Infection Bradycardia or sinus bradycardia 10 (2.4) 2 (0.5) 0 Nasopharyngitis 93 (22.1) 88 (20.5) 88 (20.4) Atrioventricular block Upper respiratory tract infection 36 (8.6) 31 (7.2) 27 (6.3) Second degree 3 (0.7) 1 (0.2) 0 Influenza 28 (6.7) 29 (6.8) 32 (7.4) First degree 2 (0.5) 1 (0.2) 0 Infection Urinary tract infection 24 (5.7) 26 (6.1) 22 (5.1) Appendicitis 2 (0.5) 0 2 (0.5) Herpesvirus infection 23 (5.5) 9 (2.1) 12 (2.8) Herpesvirus infection 3 (0.7) 1 (0.2) 1 (0.2) Nervous system disorder Neoplasm Headache 96 (22.9) 99 (23.1) 88 (20.4) Basal-cell carcinoma 2 (0.5) 3 (0.7) 1 (0.2) Dizziness 23 (5.5) 24 (5.6) 21 (4.9) Melanoma (including in situ) 0 3 (0.7) 0 General disorder Breast cancer (including in situ) 2 (0.5) 2 (0.5) 0 Fatigue 59 (14.0) 44 (10.3) 45 (10.4) Respiratory disorder Pyrexia 15 (3.6) 18 (4.2) 77 (17.9) Dyspnea 2 (0.5) 0 0 Influenza-like illness 15 (3.6) 15 (3.5) 159 (36.9) Gastrointestinal disorder * Listed are all adverse events that occurred in more than 5% of patients in any study group (with the exception of lym- phocytopenia), in decreasing order of total frequency. Listed serious adverse events occurred in at least two patients in Diarrhea 35 (8.3) 32 (7.5) 21 (4.9) any study group. † The two deaths in the group that received fingolimod at a dose of 1.25 mg were caused by disseminated primary vari- Nausea Musculoskeletal disorder 28 (6.7) 40 (9.3) 29 (6.7) TRANSFORMSの副作用; cella zoster infection and herpes simplex encephalitis. Back pain 27 (6.4) 26 (6.1) 23 (5.3) Limb pain 20 (4.8) 21 (4.9) 28 (6.5) 徐脈, this is one of the largest studies in- further evaluation in the 2-year, placebo-controlled Although 不整脈, 帯状疱疹のリスクが上昇. volving patients with multiple sclerosis to date, phase 3 trials. Arthralgia 17 (4.0) 12 (2.8) 24 (5.6) a potential shortcoming is that rare or late-appear- Myalgia 14 (3.3) 14 (3.3) 44 (10.2) 基底細胞癌やメラノーマ, ing adverse events may not have been detected Supported by Novartis Pharma. Presented in part at the annual meetings of the American Respiratory disorder because of their low incidence and the 1-year study Academy of Neurology, Seattle, in April 2009, and of the Euro- pean Committee for Treatment and Research in Multiple Sclero- Cough 30 (7.1) 20 (4.7) 16 (3.7) 乳癌のリスクにもなり得る duration. Integrated analyses of data from other sis, Dusseldorf, Germany, in September 2009. phase 3 studies and from the extensions of the Dr. Cohen reports receiving consulting fees from Biogen Idec, Dyspnea 22 (5.2) 8 (1.9) 7 (1.6) phase 2 and phase 3 studies will help refine the Novartis, EMD Serono, and Teva, lecture fees from Sanofi- Neoplasm Aventis and Waterfront Media, and research support from Gen- safety profile of fingolimod, including a possible zyme, Novartis, and Teva; Dr. Barkhof, receiving consulting fees Melanocytic nevus 42 (10.0) 28 (6.5) 24 (5.6) increase in the risk of cancer. from Bayer Schering, Serono, Sanofi-Aventis, AstraZeneca, Ge- Psychiatric disorder 定期的なLabのチェック, An oral treatment option for relapsing–remit- nentech, Novartis, Biogen Idec, Lundbeck, Talecris, Roche, Wy- eth, and MediciNova and lecture fees from Bayer Schering and Depression 18 (4.3) 21 (4.9) 32 (7.4) ting multiple sclerosis is highly desirable to im- Serono; Dr. Comi, receiving consulting fees from Merck Serono, Vascular disorder 眼科診察,VZVの注意, 癌の注意が必要. prove convenience, diminish side effects, and Novartis, Sanofi-Aventis, and Teva and lecture fees from Bayer, improve compliance.32-34 This study showed that Biogen-Dompé, Novartis, Merck Serono, Sanofi-Aventis, and Hypertension 21 (5.0) 16 (3.7) 8 (1.9) Teva; Dr. Hartung, receiving consulting and lecture fees from once-daily oral fingolimod had superior efficacy Bayer Schering, Biogen Idec, Merck Serono, and Teva, consulting Abnormal laboratory value to interferon beta-1a administered by weekly in- fees from Novartis, and grant support from Biogen Idec and Alanine aminotransferase increased 24 (5.7) 28 (6.5) 8 (1.9) tramuscular injection. Fingolimod was associated Bayer Schering; Dr. Khatri, receiving consulting fees from Bayer, Lymphocytopenia 4 (1.0) 1 (0.2) 0 N Biogen Idec, Medtronics, Pfizer, Serono; Dr.Serono and lecture with clearly identified adverse events, some of Engl Bayer, Biogen 2010;362:387-401. fees from J Med Idec, and Teva, and Montalban, receiv-
  • 31. Mt Sinai J Med 78:176–191, 2011. • 亜急性, 慢性症状ならば, 非薬物治療から考慮. • リハビリ, Psychosocial supportを優先. • ICAP methodというものがよく使用される; Identification of symptoms; 症状を検出 Causation of symptoms; 気づかせる Alleviation of symptoms; 症状を緩和する. Prevention of complications; 予防する という方法論. • 薬物治療ならば対症療法となる.
  • 32. 180 A. B. BEN-ZACHARIA: THERAPEUTICS FOR MS SYMPTOMS Mt Sinai J Med 78:176–191, 2011. Table 3. Fatigue Medications.37 – 40 怠感はMSの2/3で認める症状. Medication Mechanism of Action Dose Side Effects Amantadine (Symmetrel) Potentiates catecholaminer- 100–200 mg Hallucinations, confusion, gic/dopaminergic insomnia, and dizziness transmission Fluoxetine (Prozac) SSRI; increases serotonin in Initial dose 10–20 mg; may Insomnia, anxiety, the brain and has an increase to higher headache, flu-like effect on energy levels dosage based on symptoms, GI symptoms, individual assessment dry mouth, somnolence, weight loss or gain, decrease in libido Modafinil (Provigil) Activates the Initial dose 100–200 mg; Cardiac contraindications hypothalamus; increases may increase up to and reduction of BCP release of 400 mg daily efficacy. Insomnia, norepinephrine and anxiety, irritability, dopamine nausea, diarrhea, palpitations. SAE: Stevens-Johnson syndrome. Armodafinil (Nuvigil) A single-isomer of 50–250 mg Headache, nausea, modafinil binds to the insomnia, dizziness. dopamine transporter Studies do not show and inhibits dopamine clinical advantages reuptake versus Provigil. Methylphenidate (Ritalin) Increases dopamine and 5–10 mg Angina, arrhythmias, norepinephrine in the palpitations, tachycardia, brain through reuptake BP/HR changes, inhibition of monoamine diaphoresis, dizziness, transporters dry mouth Amphetamine and Stimulant of CNS, as above Initial dose 5–40 mg in Anorexia, abdominal pain, dextroamphetamine divided doses; may insomnia, nervousness, composite (Adderall, increase up to 60 mg. XR emotional lability Adderall XR) formulation: 20 mg once daily. Abbreviations: BCP, birth control pills; BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HR, heart rate; SAE, serious adverse event; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
  • 33. Mt Sinai J Med 78:176–191, 2011. Table 4. Antispasticity Oral and Injectable Medications.11,37 – 39 Medication Mechanism of Action Dose Side Effects Baclofen (Lioresal) GABA agonist Initial dose 5–10 mg 2–3× Fatigue, somnolence, daily with gradual weakness, dizziness, GI titration symptoms, bladder dysfunction Tizanidine (Zanaflex) Centrally acting Initial dose 2–4 mg at Dry mouth, sedation, α2-adrenergic agonist bedtime; titrate gradually dizziness, orthostatic up to 36 mg/day hypotension, edema, drug-induced hepatitis Gabapentin A GABA analogue Initial dose 100–300 mg Dizziness, drowsiness, (Neurontin) 1–2× daily; increase peripheral edema gradually Benzodiazepines Enhances GABA with Diazepam 5 mg+ as Drowsiness, cognitive diazepam (Valium) anticonvulsant, needed; clonazepam impairment, agitation, and clonazepam muscle-relaxant, and 0.5–1 mg loss of libido (Klonopin) anxiolytic properties Dantrolene (Dantrium) Muscle relaxant that Initial dose 25 mg daily; CNS effects: speech and abolishes increase to 3–4× daily visual disturbances, excitation-contraction by 25 mg every few depression, confusion, coupling in muscle cells days, up to 100 mg hallucinations, headache, insomnia, seizures, nervousness Botulinum toxin Binds to presynaptic Dose depends on site and Weakness (Botox) calcium docking protein severity of spasticity and inhibits the release of acetylcholine at the neuromuscular junction Abbreviations: CNS, central nervous system; GABA, γ -aminobutyric acid; GI, gastrointestinal.
  • 34. OUNT SINAI JOURNAL OF MEDICINE 18 Mt Sinai J Med 78:176–191, 2011. Table 5. Neuropathic Pain Medications.37,38,41 Medication Mechanism of Action Dose Side Effects Gabapentin (Neurontin) A GABA analogue Initial dose 100–300 mg Dizziness, drowsiness, 1–2× daily; increase peripheral edema gradually based on tolerance Pregabalin (Lyrica) Increases level of neuronal Initial dose 50 mg 3× daily; Dizziness, ataxia, GABA by increasing GAD may be increased to somnolence, confusion, and modulates the influx 300 mg/day within 1 week blurred vision, peripheral of calcium based on efficacy and edema tolerability Carbamazepine Reduces polysynaptic Initial dose 200 mg twice Diplopia, dizziness, (Tegretol) responses, blocks daily; increase by up to hyponatremia, blood post-tetanic activity, and 200 mg/day weekly using dyscrasias, lethargy; may depress thalamic by a twice-daily regimen of contraindicated with inhibition of voltage-gated XR pills, or a 3–4×/day MAOIs and bone marrow sodium channels regimen of other depression formulations Topiramate (Topamax) Blockage of 25–400 mg/day Fatigue, somnolence, voltage-dependent sodium cognitive impairment channels, an augmentation of subtypes of the GABA-A receptors Oxcarbazepine Sodium channel inhibition 150–1200 mg/day Dizziness, somnolence (Trileptal) Abbreviations: GABA, γ -aminobutyric acid; GAD, glutamic acid decarboxylase; MAOI, monoamine oxidase inhibitor; XR, extended release. dysfunction.15 Bladder dysfunction in MS ranges combination of disorders. Common symptoms
  • 35. Mt Sinai J Med 78:176–191, 2011. Table 6. Bladder Medications.38,42 Medication Mechanism of Action Dose Side Effects Oxybutynin (Ditropan) Antimuscarinic properties 5 mg oral 3× daily; available Anticholinergic side effects: and spasmolytic action on as transdermal patch and dry mouth, constipation, detrusor smooth muscle XR tablets nausea, dysuria, abnormal cells; blocks PSNS vision, dizziness, somnolence Tolterodine (Detrol) A competitive muscarinic 2–4 mg XR capsule As above receptor antagonist; blocks formulation PSNS Solifenacin (Vesicare) A competitive muscarinic Initial dose 5 mg once daily; As above; contraindicated in acetylcholine receptor may increase to 10 mg liver disease, closed-angle antagonist; fewer CNS daily glaucoma, urinary effects because does not retention, prolonged QT cross BBB syndrome Darifenacin (Enablex) Muscarinic receptor blocker; Initial dose of XR tablets is As above; fewer CNS effects blocks PSNS, allowing SNS 7.5 mg once daily; may be to predominate increased to 15 mg once daily Trospium (Sanctura) Muscarinic receptor blocker; 20 mg twice daily, taken As above; fewer CNS effects blocks PSNS, allowing SNS ≥1 hour before meals or to predominate on an empty stomach Tamsulosine (Flomax) α-1 antagonist; relaxes Initial dose 0.4 mg once Dizziness, unusual bladder sphincter daily; may be increased to weakness, drowsiness, 0.8 mg daily insomnia, sexual issues, orthostatic hypotension Betanechol (Urecholine) Muscarinic receptor agonist; 25–50 mg 3–4× daily Diaphoresis, dizziness, stimulates PSNS lightheadedness, headache, flushing, increased salivation Abbreviations: BBB, blood-brain barrier; CNS, central nervous system; PSNS, parasympathetic nervous system; SNS, sympathetic nervous system; XR, extended release.
  • 36. Mt Sinai J Med 78:176–191, 2011. 186 A. B. BEN-ZACHARIA: THERAPEUTICS FOR MS SYMPTOM Table 7. Bowel Medications.37,39 Medication Mechanism of Action Dose Side Effects Sodium docusate Holds water within the stool, 100–300 mg daily in divided Abdominal cramps, gas, (Colace) providing a larger, softer doses bloating, nausea, diarrhea stool Senna (Senokot) Increases peristaltic 1–3 tablets daily, usually As above movement of the intestine, taken at night for a which forces stool out morning bowel routine Bisacodyl (Dulcolax) As above 1–3 tablets daily, usually As above taken at night for a morning bowel routine Psyllium (Metamucil) Increases the bulk and 1 packet with a full glass of As above volume of the stool, water softens the stool and stimulates intestinal motility; effective when used daily and consumed with high fluid intake Glycerin suppository Coats and softens the stool 1–2 suppositories as needed As above by slowing intestinal absorption of fecal water present as erectile dysfunction, delayed ejaculation, using sildenafil citrate (Viagra) in a crossover trial; and decreased libido, whereas in women, decreased there was no significant improvement in sexual lubrication, reduced libido or anorgasmia, and symptoms.19 Lubricants and vibratory stimulation can altered vaginal sensation are very common. Primary, be useful in women. In addition, the clitoral vacuum
  • 37. Mt Sinai J Med 78:176–191, 2011. Table 8. Sexual Dysfunction Medications.39 Medication Mechanism of Action Dose Side Effects Sildenafil (Viagra) Increases PDE, therefore 50 mg as needed Abnormal vision, diarrhea, increasing cGMP and approximately 1 hour flushing, headache, nasal causing vasodilation before sexual activity congestion, urinary tract infection; contraindicated in history of cardiac disease Vardenafil (Levitra) PDE5 inhibitor; increases Initial dose 10 mg taken As above PDE, increases cGMP, and 30–60 minutes before causes vasodilation sexual activity. Dose may be increased to maximum of 20 mg based on efficacy and side effects Tadalafil (Cialis) PDE5 inhibitor; increases Initial dose 10 mg taken As above PDE, increases cGMP, and prior to anticipated sexual causes vasodilation activity; may be increased to 20 mg or decreased to 5 mg; effective to 36 hours Intracavernous A tri-mix combination Start at a low dose and titrate Penile pain, prolonged papaverine plus therapy causing blood up as needed erections, priapism, phentolamine and vessels to expand, fibrosis prostaglandin E1 increasing blood flow penile injection throughout the body and (Trimix or Bimix) to the penis, facilitating erection Estrogens Hormonal replacement in Vaginal preparation, topical Vaginal bleeding, females; increases vaginal cream dysmenorrhea, vaginitis, moisture increases endometrial hyperplasia, clitoral sensitivity cancer, breast changes, cardiovascular effects, dizziness, urinary issues, anxiety Abbreviations: cGMP, cyclic guanosine monophosphate; PDE, phosphodiesterase.
  • 38. Table 9. Depression Medications.43 – 45 Mt Sinai J Med 78:176–191, 2011. Medication Mechanism of Action Dose Side Effects Fluoxetine (Prozac) SSRI; increases serotonin and 20–80 mg/day Anxiety, insomnia, increased alleviates mood appetite, tremors, GI symptoms, headaches, rash, and sexual dysfunction with decreased libido Sertraline (Zoloft) As above Initial dose 50 mg once daily; As above may increase up to 200 mg daily Paroxetine (Paxil) As above 10–40 mg daily or up to As above 60 mg if needed Citalopram (Celexa) As above Initial dose 20 mg once daily, As above generally with an increase to 40 mg/day Escitalopram SNRI; increases serotonin and 10–20 mg daily as needed As above (Lexapro) norepinephrine in the brain, alleviating mood Venlafaxine (Effexor) As above Initial dose 75 mg/day in 2 or As above 3 divided doses with food; may be increased to 150 or 225 mg/day if needed Duloxetine As above Total of 40 mg/day (given as As above (Cymbalta) 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily) Buproprion Dopamine and 100 mg 3×/day; XR form Anxiety, insomnia, weight (Wellbutrin) or norepinephrine reuptake 150 mg twice daily loss; may lead to seizures at (Wellbutrin SR) inhibitor; alleviates mood higher dosages Imipramine (Tofranil) TCA; increases serotonin and Initial dose 75 mg/day, Dry mouth, urinary retention, norepinephrine in the brain increased to 150 mg/day constipation, BP/HR by slowing the rate of changes reuptake Amitriptyline (Elavil) As above Initial dose 75 mg/day in As above divided doses for a total of 150 mg/day Nortriptyline As above 25 mg 3–4× daily; dosage As above (Pamelor) should begin at a low level and be increased as needed Abbreviations: BP, blood pressure; GI, gastrointestinal; HR, heart rate; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; XR, extended release.