Intern seminar --Multiple Sclerosis Presentor： Int. 蔡昇達 Supervisor： V.S. 謝奇璋 CR 陳俐文 2011.07.01
Identifying information： Name: 郭X萱 Sex: F Age: 16 y/o (高二) Chart Number: 1455xxxx Date of Admission: 2010/06/03 Occupation: 高二學生 (長榮中學) Right handed (右手寫字、拿筷子) Chief complaints ： unsteady gait for 7 days
Present Illness-1 In recent one month：(母親節那天早上開始) blurred vision (O.D.)尤其往右看時較不清楚 4 limbs and trunk numbness (先手再腳再軀幹，左手>右手，手麻到上臂、腳麻到大腿，腹部和下背部也會麻) unsteady gait and dizziness while walking Right upper limb weakness (覺得寫字的時候手變得比較沒力氣)
Present Illness-2 Recent infection (-) Trauma (-) Fever (-) Rash (-) Vomiting (-) Speech disorder (-) Urinary symptoms (-) 症狀發生於洗熱水澡時 (-) But… the symptoms were similar to 3 years ago..
Present Illness-3 三年前，國二 2007/10：早上醒來頭暈、東西會動(所以看不清楚)，尤其看右邊時、走路不穩 去年，高一，2010：早上醒來看東西會動，跟之前一樣、但不會暈，可以走路、左手手腕以下麻木，但仍可拿碗不會掉 今年高二，母親節早上：醒來，看東西會動、頭暈、不能走路、四肢麻、肚皮麻一圈
Past history Denied any systemic disease Operation： nil Birth history： GA: 39+ weeks, BBW: 2980g, G5P3, C/S Vaccination： as Taiwan schedule Drug Allergy History: No Known Drug Allergies
Social History: Smoking：Negative Drinking：Negative Betel nut：Negative Drug abuse：Negative 教育程度：高中 宗教背景：無 Family History: No any family member had unsteady gait, dizziness, numbness, weakness, or blurred vision.
Physical examination Consciousness: clear Vital signs: T/P/R: 36.8/72/18 BP=103/94 mmHg General appearance: fair Conjunctiva: not pale Sclera: not icteric Neck: stiffness (-), Meningismus (-), Brudzinski sign (-), Kernig's sign (-) Heart: regular heart beat, no murmur Chest: symmetric expansion, bilateral clear breath sound No obvious muscle atrophy Atrophy, especially first dorsal interosseus muscles
Neurological examination Mental Status: Consciousness : clear and alert Concentration : good Language: Comprehension: good Fluency: good Repetition : good Naming: good Reading: good Writing: good Speech: good JOMAC: intact
Neurological examination-cranial nerves II: pupil size: isocoric, 4.0/4.0 (R/L) light reflex : + / + (R/L) visual field: no obvious defect Visual acuity: right eye blurred (看右邊時較明顯) 於急診時眼科會診：No retina/optic nerve head abnormality. → r/o retrobulbar optic neuritis III, IV, VI: EOM: full, no limitation V: Facial sensation: symmetric Masseter/temporalis muscle power: full 右上圖 Figure 13-11. Acute optic neuritis in a patient with multiple sclerosis. The disc is swollen from an inflammatory process near the nerve head (papillitis) and the patient is virtually blind in the affected eye.
Neurological examination-cranial nerves VII: Frontal wrinkle: symmetric Nasolabial fold: symmetic No facial palsy VIII: horizontal and vertical nystagmus no hearing impairment IX, X: Uvula elevation: symmetric XI: Sternocleidomastoid muscle power: full Trapezius muscle power: full XII: Tongue protruding: no deviation Nystagmus: (+，看兩邊及上下時會出現，快速相往 central position) FFS(+，請病人一邊看一邊算 100-7 時，眼震幅度並沒有減小)
Neurological examination-motor system Muscle power: DTR: Joint position: symmetric Coordination：F-N-F test: no dysmetria Muscle tone: normotonous bilateral ankle clonus (+) Gait: slightly unsteady gait
Neurological examination-sensory system Joint position: intact decreased pinprick over right T6-L4 (6/4) T8~T10 decrease discriminative sensation Temperature: normal Vibration: normal
Neurological examination-coordination FNF: no dysmetria Heel-knee-shin: no intentional tremor Rapid alternative movement: no dysdiadochokinesia No truncal ataxia Gait: slightly unsteady Tandem gait: cannot perform Arm bounce: normal
Lab data-1
This time at 成大 There are instances in which the radiologic changes caused by recurrent small infarctions are difficult to distinguish from multiple Sclerosis. 放射科報告：Multiple small foci of hyperintensity on T2WIs and T2 FLAIR at bilateral cerebral/cerebellar white matters and cervicomedullary junction, more dominant at periventricular regions. Multiple sclerosis is favored. (2007.10.13 at 奇美) DDX： ADEM, vasculitis of unknown nature, viral encephalitis, embolic events, metastatic lesions...but less likely. Recommend clinical correlation and follow up. (by 奇美許振芳、吳德昌醫師) 三年前 at 奇美
Upper cervical NCKU spine MRI
myelopathy The myelopathy of C~T spine can explain the numbness sensation
Medulla oblongata pons The brain stem lesion may explain the nystagmus and unsteady gait → 平衡覺傳遞的徑路受損
Corpus callosum—Dawson fingers Although the lesions are usually round or oval, they often have finger-like extensions along the path of small or medium-sized blood vessels (Dawson’s fingers). → 所以此名稱不限於形容 corpus callosum cerebellum Corpus callosum—Dawson fingers 垂直 corpus callosum 的 lesion
Inflammatory MS Lesion The commonly accepted pathologic criteria of a demyelinative disease are (1) destruction of the myelin sheaths of nerve fibers with relative sparing of the other elements of nervous tissue, i.e., of axons, nerve cells, and supporting structures, as reflected by a relative lack of wallerian or secondary degeneration of fiber tracts; (2) infiltration of inflammatory cells in a perivascular and particularly paravenous distribution; → 如此圖 (3) a distribution of lesions that is primarily in white matter, either in multiple small disseminated foci or in larger foci spreading from one or more centers.
Trojano, M. Nature Review Neurology 7, 251–252 (2011) CIS = clinically isolated syndrome CDMS= clinically definite MS 2010 年版較簡化，而準確率只有些許下降：70.0% ： 71.6% (2001年版 ) The key DIT principle of two episodes of disease activity separated by a minimum of 30 days, which had been the foundation of MS diagnosis for 50 years, seems to have become less relevant. → 即現在的 DIT 不需間隔到 30 天，用有無顯影的 lesion 同時出現即可 (因為退顯影的期間從 4 週~ 6個月不等) As evidence emerges for early onset of axonal injury, brain atrophy and signs of cognitive dysfunction in MS, early initiation of drugs—and therefore an early diagnosis —becomes imperative (重要的). → MS 早期診斷、早期開始用藥的重要性 → 新的簡單 criteria 較容易達成此目標，而且成本比較便宜 Trojano, M. Nature Review Neurology 7, 251–252 (2011) 22
Adams principles of neurology 8th edition Other tests BAEP： no evidence of peripheral or central auditory pathway involvement. (at 奇美) VEP： normal VEP studies. (at 奇美) Do MRI again + MRA Check C3/C4/ANA/anti-dsDNA to rule out SLE SLE: In some instances the CNS manifestations resemble multiple sclerosis, especially when there is an optic neuritis and myelopathy. The presence of serum antinuclear antibodies is of help in the differentation of lupus erythematosus but in itself does not establish the diagnosis. ？ ？EP ？ Adams principles of neurology 8th edition
Treatment Pulse therapy： And followed by oral steroid： Solumedrol 1000mg in N/S 120ml ivdrip for 1hr qd x 3天 (on 6/4,6/5,6/6) And followed by oral steroid： Prednisolone (5) 4# po tid, since 6/7 (60mg/day) Monitor Blood pressure and check dextrose qd → for steroid therapy side effects → not happened
Discussion Weakness in one or more limbs (50%) Numbness in one or more limbs (45%) Optic neuritis (20%) Unsteady gait (15%) Diplopia (10%) Vertigo or dizziness (5%) Classic features include motor weakness, paraparesis, paresthesias, loss of sight, diplopia, nystagmus, dysarthria, intention tremor, ataxia, impairment of deep sensation, and bladder dysfunction.
Adams principles of neurology 8th edition Relative prevalence of the major neurologic disorders in the United States 此書為 neurology 之聖經 MS is among the most venerable (令人尊敬的) of neurologic diseases and one of the most important by virtue of (因…的德行) its frequency, chronicity, and tendency to attack young adults. → 不算少見 + 慢性 + 發生於年輕人 = MS 是個讓人尊敬的疾病 Adams principles of neurology 8th edition 26
雖然已是 40 年前的統計，但現在之趨勢仍然如此 15 歲之前，住在高緯度地區的人比住在低緯度地區的人有較高的機會得到多發性硬化症。
Diagnosis by exclusion！！！ Meningovascular syphilis → history certain rare forms of cerebral arteritis → MRA vascular malformations → MRA brain lymphoma → bronchopulmonary infection lupus erythematosus → ANA, anti-dsDNA, C3/C4, optic nerve 較少影響到 antiphospholipid antibody syndrome → ANA Behcet disease → recurrent iridocyclitis and meningitis, mucous membrane ulcers of mouth and genitalia cardiogenic embolism vascular malformations such as cavernous angiomas of the brainstem or spinal cord with multiple episodes of bleeding 因為需鑑別的疾病很多，難以列出一個 standard clinical criteria for MS Conversely, between 5 and 10 percent of MS patients have antinuclear or anti–double stranded DNA antibodies without signs of lupus, but the significance of this finding is not at all clear. In addition, it has been pointed out that the relatives of patients with MS have a higher than expected incidence of autoantibodies of various types, suggesting an as yet unproved connection between autoimmune disease and MS. Adams principles of neurology 8th edition
Relapsing-remitting episodes ADEM MS Incidence 0.4/100, 000 2.5/100,000 in children Prodromal infection Viral infection(75%), Mycoplasma, Chlamydia, Rickettsia… X Clinical manifestations Polyfocal neurological deficits : acute hemiparesis, ataxia, cranial neuropathy (optic neuritis), spinal cord dysfunction + encephalopathy : 1. Behavior change 2.Conscious change 50-70%: Polyysmptomatic 30-50% Monosymptomatic - 62% motor dysfunction - 43% optic neuritis(higher in Asia) - 15-30% sensory dysfunction - 25% brainstem symptoms) - 5-15% ataxia Fever, seizure, meningism, Ataxia, areflexia Relapsing-remitting episodes CSF WBC ↑(<50/cmm) Protein ↑ Oligoclonal band(29%) WBC↑(<30/cmm) Oligoclonal band (60-90% MS) 2008/01/29 家醫科 R4 黃琬茹
ADEM MS MRI VEP Abnormal (in p’t with optic neuritis) Abnormal (56%) Ill-defined, Large (>1 to 2 cm in size) multifocal, hyperintense, bilateral, asymmetric lesions in the supratentorial or infratentorial white matter. Deep gray matter (basal ganglion, thalamus) Spinal cord MRI may show confluent intramedullary lesion(s) Disseminated in space over time Peri-ventricular white matter involved Optic neuritis Corpus callosum involved Well-defined Spinal cord involvement VEP Abnormal (in p’t with optic neuritis) Abnormal (56%) EEG Increased background slow wave X Recurrence Usually recover completely <10% (most within 1 month) >45% relapse (First attack <10y/o mean 6years First attack > 10y/o mean 1 year) >20% MS (>1month, >2Non-AEDM ) 2008/01/29 家醫科 R4 黃琬茹
ADEM Brain MRI T2 2008/01/29 家醫科 R4 黃琬茹
Acute disseminated encephalomyelitis 成大小兒科 ADEM：MS = 3：4 (from 電子病歷系統 病歷搜尋) Acute disseminated encephalomyelitis 毛○齡 18y/o, F 15歲：ataxia and headache, visual torsion(看東西斜向一邊), progressive ataxia, cannot walk or stand, progressive L't hemiplegia, L't dysmetria, and R't ankle clonus 劉○睿 11y/o, M 7歲：fever up to 38C, off and on for 3-4 weeks, accompanied with headache, productive cough, rhinorrhea, and abdominal pain → mycoplasma pneumonia with AOM → 出院後仍然 headache, vomiting + blurred vision (看電視看不清楚，寫字要很靠近桌子才看得到，走路常跌倒) 陳○霈 8y/o, F 5歲：Abdominal pain started two weeks ago with nausea and vomiting + fever → irritable crying + behavioral change → mutism → delirium, muscle power decrease → Hamiballismus-like movement (basal ganglion involvement) Multiple sclerosis 盧○翎 20y/o, F 16歲(>3次)：seizure-like movement, consciousness disturbance, blurred vision, dizziness, right ankle weakness 謝○庭 15歲(第1次)：sudden onset of bilateral blurred vision 15歲(第2次)：sudden onset of lower limbs weakness 16歲(第3次)：bilateral lower legs paresthesia and weakness 龔○娜 16y/o, F 15歲： right lower limb mild weakness and numbness over lateral side Hamiballismus-like movement: 像舞蹈症一般亂揮動四肢 (單側肢體) From Wiki： Hemiballismus is usually characterized by involuntary flinging motions of the extremities. The movements are often violent and have wide amplitudes of motion. They are continuous and random and can involve proximal and/or distal muscles on one side of the body. Some cases even include the facial muscles. It is common for arms and legs to move together. The more a patient is active, the more the movements increase. With relaxation comes a decrease in movements. The name 'hemiballismus' literally means 'half ballistic (失去理智的)', referring to the violent, flailing (連續的) movements observed on one side of the body.
Multiple Sclerosis - Pathology Optic chiasm Medulla oblongata Occipital lobe Pons
luxol fast blue and periodic acid–Schiff myelin stain neurofilament staining for axons ventricle ventricle Figure 3. Photomicrographs of a Chronic Multiple Sclerosis Plaque. In Panel A, a well-demarcated hypocellular region of myelin loss is evident in the periventricular white matter (luxol fast blue and periodic acid–Schiff myelin stain, ¬15). In Panel B, neurofilament staining for axons in the same lesion demon- strates a reduction in axonal density (¬15). myelin loss Axonal density reduction 2000 NEJM Volume 343 Number 13
Remyelination NAWM = normal-appearing white matter Figure 5. Remyelination in a Lesion Associated with Chronic Multiple Sclerosis. The area stained pale blue (indicated by the asterisk) repre- sents a region of partial remyelination (a shadow plaque) along the periventricular edge of a lesion in a patient with chronic multiple sclerosis (luxol fast blue and periodic acid–Schiff my- elin stain, ¬15). NAWM denotes normal-appearing white matter. NAWM = normal-appearing white matter 2000 NEJM Volume 343 Number 13
Steroid Interferon- b (1a、1b) = Immuno-modulator Plasma exchange (急性期) IVIG Natalizumab 可與白血球上的 α 4 - integrin 結合，進而阻擾了 α 4 - integrin 與血管壁上的血管細胞黏著分子 -1 (vascular cell adhesion molecule –1, VCAM-1) 的相互作用，這樣子白血球較不易鑽出血管內皮到組織中引起發炎反應。另外它也可影響 α 4 - integrin 與細胞外基質與腦實質細胞中其它分子的作用，進而抑制吸引更多的發炎細胞。 (2010 NEJM) Fingolimod是一全新治療機轉，以口服方式投予，藉由調節『鞘氨酸1-磷酸鹽受體(sphingosine 1-phosphate，S1P receptor)』來治療復發型多發性硬化症。fingolimod以淋巴球上S1P受體擷抗劑的方式，阻斷淋巴球自淋巴結中移出的能力，造成淋巴球之重分佈而非耗損，以減少致病性淋巴球細胞滲透至中樞神經系統中，引起神經發炎及神經組織損傷。 (2010 NEJM) Cladribine 原本是治療髮樣細胞白血病 (Hairy cell leukemia) 的化療藥物，為一個嘌呤類似物，能干擾細胞合成DNA的能力，進而達到阻止癌細胞分裂的效果，這種抗癌製劑，也能透過抑制白血球DNA的代謝與分裂進而抑制免疫系統。 IFN β的作用有一部分即是拮抗 IFN γ的作用，因為 IFN γ是一種很強的免疫活化劑。 IFN β的免疫調節作用相當複雜，它對 T 細胞，血管內膜及小神經膠質細胞都具有免疫調節的功能。目前 IFN β為何對 MS 有療效仍然不清楚，不過可能與抑制 T 細胞的增殖及移動，降低中樞神經的免疫反應有關。 Nature Reviews Drug Discovery 7, 909-925 (November 2008)
Types of Multiple Sclerosis Benign MS: episodes of relatively mild sensory symptoms, followed each time by complete recovery Relapsing-remitting MS: episodes of exacerbations and remissions during which some symptoms remain unresolved Primary progressive MS: gradually worsening symptoms that is not punctuated by episodes of relapse and recovery Secondary progressive MS: gradually worsening symptoms as in primary progressive MS, but succeeds the typical relapse-remitting pattern 40 歲以後發病者多為第三種類型： primary progressive MS (Adam’s principle)
Clinical course and prognosis The average relapse rate is 0.3 to 0.4 attacks per year (calculate by McAlpine and Compston) McAlpine’s cases：(第一次發現症狀之後) 30 %： 1 年內 relapse 20%： 1~2 年間 relapse 20%： 5~9 年 10%： 10~30年 平均餘命： > 30 年 注意： highly variable Contrary to commonly held opinion, pregnancy does not have an adverse effect on MS. In fact, pregnancy is typically associated with clinical stability or even with improvement (as it is in a number of autoimmune diseases). An extensive study of 269 pregnancies by Confavreux and colleagues established a rate of relapse of 0.7 per woman per year before pregnancy and rates of 0.5 in the first, 0.6 in the second, and 0.2 in the third trimester, the rate then increasing substantially to 1.2 in the first 3 months postpartum. → 結論：懷孕不會提升復發的機率，反而會使之下降，故患者不需擔心。 A 60-year appraisal of the resident population of Rochester, Minnesota, disclosed that 74 percent of patients with MS survived 25 years, as compared with 86 percent of the general population. At the end of 25 years, one-third of the surviving patients were still working and two-thirds were still ambulatory (Percy et al). → 在生命最後的 25年，三分之一的患者仍可工作，三分之二的患者仍可行走。 Adams principles of neurology 8th edition
Thanks for your attention！ Take home message Multiple sclerosis → demyelinating disease Diagnosis by exclusion May be an autoimmune disease Chronic clinical course Thanks for your attention！
References Adams principles of neurology 8th edition 神經科蔡子同老師上課講義 Uptodate Trojano, M. Nature Review Neurology 7, 251–252 (2011) 2000 NEJM Volume 343 Number 13 Nature Reviews Drug Discovery 7, 909-925 (November 2008) 台大醫院多發性硬化症之友 光田綜合醫院
Mitoxantrone、Cladribine (immuno-suppressant) 單株抗體 Natalizumab Fingolimod Plasma exchange (急性期) Interferon- b (1a、1b) = Immuno-modulator Multiple sclerosis is generally believed to be an immune-mediated disorder that occurs in genetically susceptible people. Furthermore, the lesions of chronic multiple sclerosis reportedly contain substantial numbers of oligodendrocyte precursor cells. Thus, central nervous system myelin can be repaired, and mechanisms that promote endogenous remyelination may represent a feasible therapeutic strategy. → lesion 處還有很多的 oligodendrocyte 可使 myelin再生 多發性硬化症是一種『多因素』疾病，『多因素』，意味著不只一種原因與此疾病有關，許多種因素必須恰巧遇在一起，才會導致多發性硬化症的發生。病毒很有可能是其中的一個因素，有特殊基因體質的人，受到某些病毒感染，可能會導致免疫系統的異常，而引發多發性硬化症。雖然到目前為止，並沒有在多發性硬化症患者身上發現固定的一種病毒。許多研究人員仍相信應該有某種病毒來『啟動』不正常的免疫反應。所以，現在有許多研究在努力尋找這隻多發性硬化症的『啟動病毒』。 雖然多發性硬化症未證實由病毒引起，確實有病毒可以引起其他的脫髓鞘疾病。熱帶痙攣性下肢無力 (Tropical spastic paraparesis) ，就是病毒引起脫髓鞘的例子。找尋誘發多發性硬化症病毒的努力仍持續進行著。曾被考慮過，但目前已排除的病毒包括麻疹 (Rubeola) 、德國麻疹 (rubella) 、庖疹 (Herpes) 以及人類嗜 T 細胞淋巴球第一型病毒 (Human T-cell lymphotrophic, type I) 。目前密切觀察中的病毒是庖疹第六型病毒 (herpes 6 virus) ，兒童經常受到這種病毒的感染，之後會自行痊癒。很可能這個病毒誘發特別的免疫反應，但是等到免疫系統攻擊髓鞘的時候，這隻病毒早已消失不見。此外，環境因素似乎也與多發性硬化症有關。 15 歲之前，住在高緯度地區的人比住在低緯度地區的人有較高的機會得到多發性硬化症。 因為不知道免疫作用到底哪一個步驟出問題，所以有好多個研究方向，有人研究抗體，有人研究 T 細胞，有人用化療藥物來改變 T 細胞，有人用血液離析的方法將淋巴球過濾掉，有人用放射線照射淋巴組織，這種種的方法都是試圖改變多發性硬化症病人的免疫系統。 在多發性硬化症的確切原因還沒有釐清之前，很難找到根治此病的方法。然而這並不意味著我們對這個疾病束手無策，隨著時間累積的經驗與研究結果，已有針對症狀處理的策略，好讓病人能盡量維持原有的功能，讓多發性硬化症病人活的有活力、有意義、有歡樂。 2000 NEJM Volume 343 Number 13 41