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.
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;363:564 72. 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 monosymptomaticBecause 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 myelitishypotension and is contraindicated in patients withunderlying cardiac comorbidities (Van Koningsveld Bacterial infections Syphilisand Van Doorn, 2005). AbscessRehabilitation MycoplasmaAcute phase rehabilitation should include an individual- Lyme diseaseized programme of gentle strengthening, involving iso- Viral infections Encephalomyelitismetric, isotonic, isokinetic, and manual and progressiveresistive exercises. Rehabilitation should emphasize prop- Polioviruser limb positioning, posture and orthotics as well as Herpes zosternutrition. Herpes virus B RabiesPrognosisThe majority of patients will recover within weeks, but Human immunodeficiency virus30% will still have weakness after 3 years and 3% will Autoimmune Systemic lupus erythematosusrelapse. The overall mortality rate is around 3–4% (El Sjögren’s syndromeMhandi et al, 2007). SarcoidosisAcute transverse myelitis VasculitisEpidemiology Vaccinations Bacillus Calmette–GuérinThe disease has two peak incidences: between the ages Smallpoxof 10–19 years, then again between the ages of30–39 years. There have been few population-based Poliostudies of acute transverse myelitis and there appears to Other Parasitic infectionbe no real link with any identifiable patient characteris- Fungal infectiontics. There is no significant seasonal or annual fluctua- Acute multiple sclerosistion in frequency. British Journal of Hospital Medicine 2011;72:264-269
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 0·38Data 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 KIDMUSmore 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 moreT2 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 CSFAbbreviations: 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
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.
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 8Beta-interferon (IFN-β) was the ﬁrst class of therapy ARR forapproved to treat MS. IFN-β-1b (Betaseron) givensubcutaneously (SC) every other 1.6MIU 1.17 vs 8MIU 0.84回/yr) (Placebo 1.27 vs day was approvedby the FDA in 1993. Since then, 3 additional IFN-βhave 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 injection3× 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 isunknown, IFN-β drugs likely have multiple effectson 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, andat the blood-brain barrier there is down-regulation 75%が3moで減弱, production ofof adhesion molecules and decreased 消失.matrix metalloproteinases. This limits the entry ofT 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 studyshift 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 primaryfects 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-mgbo-controlled study of 1272 patients comparing the placebo group. This corresponded to a relativees 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 adsDwithin-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 monthse 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 metmary 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 inmg group, respectively, compared with 0.40 in acebo group. This corresponded to a relative 0.5-mg group and 0.16 in the thetion 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 placeboThe FREEDOMS trial was a
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 disordersAt 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 0Infections 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 0Abnormal laboratory liver-function test§ 80 (18.6) 67 (15.8) 21 (5.0) Headache 2 (0.5) 0 0Fatigue 47 (11.0) 48 (11.3) 45 (10.8) General disordersMusculoskeletal 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 disordersRespiratory 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) 0Blood 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). LymphopeniaCardiovascular 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-1aEvent 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 eventsAny 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 0Most frequently reported adverse events Cardiovascular disorderInfection 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) 0General 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- NauseaMusculoskeletal 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 AmericanRespiratory 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, consultingAbnormal 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 – 39Medication Mechanism of Action Dose Side EffectsBaclofen (Lioresal) GABA agonist Initial dose 5–10 mg 2–3× Fatigue, somnolence, daily with gradual weakness, dizziness, GI titration symptoms, bladder dysfunctionTizanidine (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 hepatitisGabapentin A GABA analogue Initial dose 100–300 mg Dizziness, drowsiness, (Neurontin) 1–2× daily; increase peripheral edema graduallyBenzodiazepines 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 propertiesDantrolene (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, nervousnessBotulinum 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 junctionAbbreviations: 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.38,42Medication Mechanism of Action Dose Side EffectsOxybutynin (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, somnolenceTolterodine (Detrol) A competitive muscarinic 2–4 mg XR capsule As above receptor antagonist; blocks formulation PSNSSolifenacin (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 syndromeDarifenacin (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 dailyTrospium (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 stomachTamsulosine (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 hypotensionBetanechol (Urecholine) Muscarinic receptor agonist; 25–50 mg 3–4× daily Diaphoresis, dizziness, stimulates PSNS lightheadedness, headache, ﬂushing, increased salivationAbbreviations: 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.39Medication Mechanism of Action Dose Side EffectsSildenaﬁl (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 diseaseVardenaﬁl (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 effectsTadalaﬁl (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 hoursIntracavernous 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 erectionEstrogens 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, anxietyAbbreviations: 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 EffectsFluoxetine (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 libidoSertraline (Zoloft) As above Initial dose 50 mg once daily; As above may increase up to 200 mg dailyParoxetine (Paxil) As above 10–40 mg daily or up to As above 60 mg if neededCitalopram (Celexa) As above Initial dose 20 mg once daily, As above generally with an increase to 40 mg/dayEscitalopram SNRI; increases serotonin and 10–20 mg daily as needed As above (Lexapro) norepinephrine in the brain, alleviating moodVenlafaxine (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 neededDuloxetine 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 dosagesImipramine (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 reuptakeAmitriptyline (Elavil) As above Initial dose 75 mg/day in As above divided doses for a total of 150 mg/dayNortriptyline As above 25 mg 3–4× daily; dosage As above (Pamelor) should begin at a low level and be increased as neededAbbreviations: BP, blood pressure; GI, gastrointestinal; HR, heart rate; SNRI, serotonin norepinephrine reuptake inhibitor;SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; XR, extended release.