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
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
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.
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
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.