脱髓鞘疾病医疗及研究管理知识分析.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,资料仅供参考,不当之处，请联系改正。,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,资料仅供参考,不当之处，请联系改正。,周文斌,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,周文斌,*,资料仅供参考,不当之处，请联系改正。,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,周文斌,*,*,资料仅供参考,不当之处，请联系改正。,周文斌,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,周文斌,*,资料仅供参考,不当之处，请联系改正。,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,周文斌,*,*,资料仅供参考,不当之处，请联系改正。,神经纤维指轴突而言，分为有髓和无髓神经纤维。,Nerve fiber or an axon,Myelinated Nerve Fiber,Unmyelinated Nerve Fiber,髓鞘,:,紧裹在有髓鞘神经轴突外面的脂质细胞膜，由髓鞘形成细胞膜组成。,Myelin is a layer that forms around nerves formed by wrapped plasma membrane of myelinization cells.,髓鞘：蛋白质,22%,，脂类,78%,Myelin,：,protein 22,and lipids 78,蛋白质,:,碱性蛋白、脂蛋白、糖蛋白等。,Protein,：,Basic protein,、,lipoprotein,、,glucoprotein,脂类,:,胆固醇、神经鞘磷脂、脑苷脂与神经节苷脂。,Lipide,：,lipide,、,sphingomyelin,、,galactosyl ceramide,、,ganglioside,生理作用,：,Physiological functions,神经冲动的快速传导；,Speeding the transmission of impulses,对神经轴突起绝缘、保护作用。,Insulation and protection of neuraxon,髓鞘系统,：髓鞘、轴索与完整的血供,Myelin system:myelin,、,axon and intact blood supply,脱髓鞘疾病,：,CNS,白质对各种有害因素的反应,Demyelinating disease,脱髓鞘脑病,Demyelinating encephalopathy,髓鞘构成缺陷性疾病,（白质营养不良症）,myelin construction deficiency syndrome Leukodystrophy,周围神经系统脱髓鞘疾病,Peripheral nerveous demyelination,CNS:White matter disease,Demyelinating:mainly acquired,MS,PML,Encephalomyelitis(ADEM),Anti-MAG Disease,CNS:White matter disease,Dysmyelinating:mainly inherited,Leukodystrophies:,ALD Alexander,Canavan disease,Krabbe Disease,MLD,Pelzaeus-Merzbacher Disease,Refsum,PNS:Neuropathies,Acquired:,mainly autoimmune,demyelinating polyneuropathies,.,Acute:,GBS,Chronic:,CIDP,Anti-MAG syndrome,Multiple Motor Neuropathy(MMN),PNS:Neuropathies,Hereditary:,mainly dysmyelinating.,HMSN/CMT,Cockayne Syndrome,Krabbe Disease,MLD,Refsum Disease,Conduction in a Demyelinated Nerve Fiber-KH,多发性硬化,Multiple Sclerosis,CNS,白质的慢性，炎性，斑块性脱髓鞘，,CD 4,+,T,细胞介导的自身免疫性疾病。,Chronic,progressive immune-mediated CNS disease,Characterized by demyelination and axonal loss,全世界病人超过,200,万。,Affecting over 2 million persons worldwide,概述,overview,最常损害部位是脑室周围白质、视神经、脊髓、脑干传导束及小脑白质。,white matter bordering the lateral ventricles,、,opticus,、,spinal cord,、,pyramidal tract and Cerebellar white matter,引起年轻成人中神经残疾的最常见疾病（美国）。,The most common disabling neurological disease of young people.,概述,overview,女性多见,Women outnumber men 2:1,缓解复发病程，逐渐加重,Progressive relapsing-remitting course,可能与早期病毒感染有关,no specific causes,viral may be responsible,概述,overview,Vit D,缺乏与,MS,MS,具有显著的地理分布特征,:,在赤道几内亚区,MS,的发生率几乎为零，在两半球随着纬度的增加而戏剧性的增加,在瑞士高海拔区,MS,发生率低，低海拔区发生率高,低纬度区阳光充足，高海拔区紫外光强度高，能够促使大量,Vit D,合成,Vit D,缺乏与,MS,VitD,能抑制,DC,分化、,Th1,细胞增殖，减少,IL-12,、,IFN-,产生,VitD,能促进调节性,T,细胞增殖，促进,IL-10,、,TGF-,分泌,概述,overview,第一次肯定了,MS,临床症状与,MS,尸检病理之间的关系；,第一次提出了“硬化与斑块”的概念；,sclerose en plaques,第一个认定,MS,是一种独立的疾病；,第一个提出,MS,的诊断标准,-,即“,Chacot,三联症”；,Triad:nystagmus,intention tremor,scanning speech,他还对,MS,的病理特征进行了详细的描述，如,髓鞘脱失,demyelination,胶质纤维增生,macrophages,等。,病因、发病机制,Etiology,：,免疫,immunity,：,EAE,Experimental allergic encephalomyelitis,，致敏（活化）的抗原特异性的,CD4+T,细胞。,The activated antigenic specifically CD4+cell.,病毒,virus,：,分 子模拟机制,molecule mimicry mechanism,激发自身免 疫反应,autoimmune etiology,遗传,heredity,：单卵双生子、,HLA,EAE,：实验性自身免疫性脑脊髓炎,Experimental allergic encephalomyelitis,使用,MBP,或,PLP,免疫,Lewis,大鼠；,Immunizing the Lewis rat by MBP and PLP,MBP,致敏的,T,细胞转输给正常大鼠。,transfusion the MBP activated Tc to normal rats,病因、发病机制,Etiology,：,初始,T,细胞,Th2,Th1,巨噬细胞,IL-2,IL-12,IFN-,TNF,B,细胞,相互抑制,IL-4,IL-5,IL-10,IL-12,TGF-,初始,CD4,+,T,细胞分化,Th1,Th2,Th1,Th2,正常,MS,Th1/Th2,平衡,Th1,细胞,：,IL-2,、,IFN-,等,Th2,细胞,：,IL-4,、,IL-6,等,Th17,细胞,：,IL-17,巨噬细胞、,DC,：,IL-12,、,IL-23,Th1/Th2,平衡,IL,-1,2,主要由树突状细胞、巨噬细胞,产生，是由,p35及p40 2条多肽链以二硫键的形式结合在一起的异二聚体型,（,IL-12 p70,）。,IL-12,能刺激,Th1,细胞增殖,诱导免疫效应细胞产生,IFN-,。,IFN-,可调节细胞因子,“,级联作用模式,”,增强免疫应答。,Th1/Th2,平衡,IL-12,是,Th1,分化的关键因子，然而,IL-12,基因敲除小鼠仍能产生,EAE,；,IFN-,是,Th1,的重要致病因子，然而,IFN-,基因敲除,仍能诱导产生,EAE,，而且恢复缓慢。,其他致病机制？,Th1/Th2,平衡,Thl7,细胞是新近发现的辅助性,CD4+,细胞，因其独特的表型特征和分泌,IL-17,而得名。,IL-17,具有强大的招募中性粒细胞及促进多种细胞因子释放的作用，处于固有免疫和适应性免疫反应的交接面。,Th17,细胞,IL-17,在,EAE,模型小鼠急性期的外周血和脑脊液中都有较高水平的表达,IL-17-/-,小鼠对,EAE,不敏感，抗,IL-17,抗体可以使,EAE,症状明显减轻。,多发性硬化病人的脑组织、血的单核细胞以及脑脊液中,IL-17,的,mRNA,及蛋白的表达均明显升高。,Th17,细胞,CD4+CD25+,调节性,T,细胞,是具有免疫调节功能的,T,细胞亚群，具有,免疫无能,和,免疫抑制,两大功能特征。,MS,患者外周血,CD4+CD25+T,细胞数量变化不明显，但,CD4+CD25+T,细胞抑制活性降低。,调节性,T,细胞,Th17,、,Th1,、,Th2,、,CD4+CD25+T,细胞这,4,种,T,细胞亚群及细胞因子相互作用、此消彼长组成的复杂网络在,MS/EAE,的疾病发展进展中起重要作用,免疫反应背离,Th2,、,CD4+CD25+T,细胞，而向,Th1,、,Th17,细胞偏移是自身免疫性疾病发生发展的重要机制,Antibodies in MS,OCBs:90%patients,temporal and clonal invariance,Restricted B-cell VH repertoire in MS CSF and MS lesions antigen-driven response,List of autoantibodies in MS ever-expanding,High titre antibodies against myelin Ag in MS are inconsistent and unrelated to clinical outcomes.,OCBs are not eliminated by RTX,Autoantibody-mediated disorders of the CNS?,1.Antibodies directed towards a relevant cell surface epitope,2.Immunotherapy and PLEX result in a reduction in antibody titre associated with amelioration of disease,3.Passive transfer of the immunoglobulin(Ig)fraction from an affected patient reproduces the clinical phenotype in an experimental animal.,Autoantibodies may be negative regulators of inflammation(lipid antigen:antiphosphatidylcholine,病理,pathology,CNS,白质内有多发性脱髓鞘斑块，围绕小静脉分布，血管周围袖套状、淋巴细胞为主的浸润，引起髓鞘的崩解，可伴有轴索的破坏,。,Peri-venule distribution of Demyelinating Plaques occur anywhere within the white matter of the CNS.cuffs of lymphocytes around small blood vessels,damage of myelin sheath and destruction of axis-cylinder.,脑、脊髓和视神经常有萎缩。,The atrophy of brain,、,spinal cord and optical nerve.,晚期星状细胞增生、神经胶质形成,硬化斑。,Proliferation of astrocytes,sclerosis plaques with glial scar formation in the late phase,病理,pathology,Top:Coronal brain section showing numerous plaques of demyelination,particularly in the periventricular region.Bottom:The corresponding areas show decreased black staining for myelin and increased gliosis(dark staining).,It is a section of brain stained for myelin(blue).The plaques of demyelination appear as well-demarcated pale areas with a central blood vessel.,It is a longitudinal section of optic nerve from a patient with multiple sclerosis.The pale area to the left is demyelinated and there is sharp demarcation from the myelinated area to the right.,It is section of occipital lobe stained for myelin.The central white matter is pale due to lack of myelin.,It is a cross section of pons from a case of central pontine myelinolysis,stained for myelin.The pale area in the middle is an area of demyelination.,临床表现,Clinical Presentation,发病年龄多为,20-40,岁,general onset is common between the ages of 20-40,；,多为静止性、亚急性起病，临床征象提示病灶多发，病程多波动，常有自然缓解及复发。,可累及视神经,optical nerve,、脊髓,spinal cord,、脑干,Brainstem,、小脑,cerebellum,及大脑的白质,white matter of brain,首发症状为一个或多个肢体无力或麻木；单眼或双眼视力障碍，或 复视,.,T,he,first clinical event including the somatasthenia or the anesthesia of one or more limbs,vision disorder in simple eye or two,and ambiopia.,临床表现,Clinical Presentation,颅神经功能障碍：视神经、视交叉、脑干,Damage of encephalic nerves nerve:optical nerve,、,chiasm opticum,、,brainstem,视神经损害最常见：多为单侧性，球后视神经炎，可部分恢复，无视网膜脱落，视乳头出血少见。,Damage of optic nerve,：,Typically unilateral retrobulbar neuritis,Some recovery expected,No retinal exudates,Disc hemorrhages are infrequent.,临床表现,Clinical Presentation,眼底检查早期可见视乳头水肿或正常，晚期出现视神经萎缩。,眼球运动,ocular movement,：,核间性眼肌麻痹,internuclear ophthalmoplegia,：内侧纵束,fasciculus longitudinalis medialis,外展神经,、动眼神经,，可导致复视,ambiopia,、眼球震颤,nystagmus,、眼球运动受限,limitation of ocular movement,。,临床表现,Clinical Presentation,面部感觉障碍,disability of facial perception,、面瘫,facial paralysis,眩晕,dizzy,吞咽困难,dysphagia,临床表现,Clinical Presentation,脊髓损害,Damage of spinal cord,：,脊髓后柱或脊髓丘脑束病变，多见于颈髓。,posterior column of spinal cord orposterior column of spinal cord,especially in cervical cord,不完全的感觉及运动障碍，感觉障碍更多,Partial sensory or motor disfuncion,Sensory more common,临床表现,Clinical Presentation,感觉障碍,sensory disability,：麻木、疼痛、瘙痒，浅感觉减退，深感觉障碍,anaesthesia,、,pain,、,pruritus,、,decreased superficial sensation,、,deep sensation disability,Lhermittes,征,Lhermittes sign,：屈颈时出现从背部放射至足底或双下肢的放射性疼痛，可为闪电感。,大小便功能障碍常见，可有束带感。,Bowel and bladder dysfunctions are common,with band-like pressure,临床表现,Clinical Presentation,肢体无力：一个或多个肢体无力，下肢比上肢重，不对称性瘫痪。,疲劳,运动障碍：,motor disorder,痉挛性瘫痪,:,motor disorder,小脑性共济失调,:,cerebellar ataxia,感觉性共济失调,:,sensory ataxia,临床表现,Clinical Presentation,小脑,Cerebellum,：,小脑性震颤，共济失调，小脑性眼震,Cerebellar tremor,、,ataxia,、,cerebellar nystagmus,。,临床表现,Clinical Presentation,精神症状和认知功能障碍,表现为抑郁、易怒和脾气暴躁,记忆力减退,发作性症状,强直性痉挛，痛性痉挛,三叉神经痛,常见：,运动乏力、感觉异常、视力下降与复视,Common:debility,、,paresthesia and ambiopia,。,两个重要体征：,核间性眼肌麻痹、眼球震颤,。,Two important signs:internuclear ophthalmoplegia,、,nystaxis,临床表现,Symptoms of MS,少见：认知障碍、癫痫、神志障碍。,Few,:,cognitive dysfunction,epilepsia,confused state of mind.,Charcot,三联征：共济失调（眼球震颤）、构音障碍（吟诗样语言）及意向性震颤。,Charcot Triad,：,dystaxia,dysarthria and Intention myoclonus,临床表现,Symptoms of MS,脑脊液,cerebrospinal fluid,寡克隆带,oligoclonal band,IgG,指数,IgG exponent,髓鞘碱性蛋白,myelin basic protein,电生理检测,Electrophysiology detection,诱发电位,evoked potential,辅助检查,Laboratory Findings,Typical of MS,Normal CSF glucose,Normal or mildly elevated CSF protein,Absent red blood cells,Small number of mononuclear white cells,Evidence of intrathecal antibody production,Increased IgG index or IgG synthesis rate,Oligoclonal bands,Increased free kappa light chains,MRI,T1,反映了质子置于磁场中产生磁化所需的时间，即继,90,度,RF,质子从纵向磁化转为横向磁化之后恢复到纵向磁化平衡状态所需时间。,T2,弛豫时间，表示在完全均衡的外磁场中横向磁化所维持的时间。,辅助检查,Laboratory Findings,T1,像，,多见于两侧脑室旁、尤以两侧前角及后角周围可见多发散在类圆形或融合性斑块状形态不规则的低信号区，,与脑室壁垂直，,无占位效应。,T2,为高信号。,辅助检查,Laboratory Findings,根据病灶形态、信号，可以分为急性病灶和慢性病灶。,急性病灶：,1、呈卵圆形或圆形，有明显膨胀感，边界清晰。,2、,T1WI,呈低或略低信号，周围可见等或峪高信号带。,3、,T2wI,病灶可分两部分，中央呈卵圆形或圆形高信号，有膨胀感，拟”泡”状，类似一个“核心”。周围呈环形或片状中等程度高信号，类似“晕环”。即与内部病灶有信号上的差异，为“核心,+,晕环”征象,推测中央高信号“核心”病理上为脱髓髓，而周围“晕环”为炎症及水肿。,急性期，,TlwI,低信号相当于髓鞘的脱失及不伴有结构损坏的血管源性水肿，随着髓鞘组织的再生和炎性反应的消退，,T1wI,低信号会消失。,慢性病灶也可分为两种，一为大体对称性的病灶，分布于侧脑室旁，呈细小点状或较小片状，部分融合成较大片状，病灶有收缩感，边缘较锐利，信号较均匀，周围无晕环征象，增强后无明确强化灶，但病变区可呈现片状淡薄高信号,另一种病灶分布较分散，额、顶叶，侧脑室旁，脑干等处都有，呈条状或小片状，同样有收缩感，边缘较锐利，信号均匀，增强后无强化,慢性,MS,病灶呈不规则条状、斑片状，有收缩感，,T1wI,呈等或轻微至中等程度低信号，,T2WI,呈高信号，病灶有时边界欠清。,有些慢性病灶,T1wI,信号很低，呈所谓“黑洞”状，可能标志着严重的、不可逆的组织结构破坏。,图lA、B MS单发病灶。病灶分别位于延髓后方、左侧小脑半球，TlwI呈略低信,号，T2W!呈高信号。,图,2 MS,多发病灶。横断面平扫,PDWI,、增强,T1wI,。多发病灶位于两侧脑室旁、右侧颞叶及胼胝体。,图,3 MS,多发病灶。病灶弥漫，无法确切记数，呈“自质变脏征”。,图4 MS大病灶。横断面平扫T2WI、增强T1WI。右侧额叶白质内-r2wi高信号影,增强后见边缘近弓形强化，病灶无占位效应。,图5 MS急性病灶。横断面平扫T1WI、T2WI、增强T1wI。T2WI呈“核心+晕环”征象，增强后见环形、弓形强化及无强化病灶，提示不同时期病灶同时存在。,图,6,A,、,B MS,慢性病灶。多发病灶分别呈近对称分布于两侧脑室旁及散在分布于额顶叶、侧脑室旁、脑干等，呈小条、片状，有收缩感，同时显示全脑萎缩。,图7 颈髓、胸髓、颈胸髓MS。矢状面平扫T2WI，分别见颈、胸髓粗细正常或不同程度增粗，髓内见条状T2WI高信号影。,图,8,脊髓,MS,。横断面,T2W1,平扫。分别见单发及多发病灶。,Nicknamed“black holes,”the areas of hypointensity seen on T1-weighted images are believed to indicate that MS is a disease not only of demyelination but also of axonal destruction,This MRI scan with gadolinium enhancement shows active plaques(bright areas).,女性,41,岁，半个月前开哭笑无常，站立不稳，双眼视力下降。,多发性硬化,MRI features that suggest MS,4 white matter lesions 3mm in diameter,3 white matter lesions,of which 1 is periventricular,Lesions 6 mm,Ovoid lesions oriented perpendicular to the ventricles,Brainstem lesions,Open ring appearance on gadolinium-enhanced T1-weighted images,Differential diagnosis,Infection,:,Lyme disease,syphilis,progressive multifocal leukoencephalopathy,HIV,HTLV-1 leukodystrophy,Inflammatory,:,SLE,、,Sjogren,、,Behcet,vasculitis,sarcoidosis,Metabolic,:,Vitamin B12 deficiency,lysosomal disorders,Adrenoleukodystrophy,mitochondrial disorders,other genetic disorders,Differential diagnosis,Differential diagnosis,Neoplastic,:CNS lymphoma,Metastatic cancer,Paraneoplastic syndrome,Primary brain tumor,Spinal disease,:Vascular malformations,degenerative spinal disease,Differential diagnosis,Vascular,Antiphospholipid syndrome,CADASIL,Eales disease,Cerebrovascular disease,Retrocochlear vasculopathy of Susa,Migraine,Vasculitis,发作、复发（,attack,，,exacerbation,，,relapse,）：,神经病学功能障碍表现为一种或多种临床表现（症状和体征），持续,24h,以上，即为一次发作，可以仅为自己主观感觉或为患者回忆。,One episode is one or more symptoms or signs of the neurological dysfunction last at least 24 hours,which can be the feeling and recollection of the patient.,诊断标准和分类标准,多发性硬化的定义,definition,：,时间上多发是指有,2,次或,2,次以上发作；,multiple in temporal means two or more distinct episodes of symptoms,诊断标准和分类标准,空间是指,CNS,白质有,2,个或,2,个以上部位病变。硬化是指病理上,CNS,中，在炎症脱髓鞘基础上，,multiple in spatial requires two or more lesions of the brain and spinal cord.Sclerosis means the sclerosis plaques with glial scar formation in the demyelinated inflammatory disease of CNS.,由于胶质增生等修复过程而于局部形成硬化斑块。,急性发作（,an acute episode of new disease activity,）指新病灶的出现或老病灶的重新活跃。,亚临床病灶（,subclinical or paraclnical,）病理上和上发现的新、老病灶，在临床上不一定有或曾有过相应的症状和体征。,诊断标准和分类标准,可明确亚临床病灶的方法：,热水浴、诱发电位、和或特殊的泌尿科检查。,the method of definite subclinical or paraclinical lesion hot bath test,EP,、,or special examination of urology,诊断标准和分类标准,缓解,Remission,：次发作必须累及中枢神经系统不同部位，次缓解至少持续个月。,Two Episodes of symptoms must be attributable to involvement of 2 or more parts of the brain and spinal cord.One remission must last at least one month.,回忆性资料,recallment data,：,岁以下无颈椎病而有,hermitte,征。,person with Lhermitte sign under 50 have no cervical syndrome,岁以前典型的视神经炎,typical optic neuritis under 50,诊断标准和分类标准,不同部位的病变,Various areas of lesion,：,大脑皮层下白质、小脑、脑干、脊髓和视神经各算一个部位。,white matter,cerebellum,brainstem,optic nerve and spinal cord.,不同的症状和体征不能用单一病灶来解释，称之为不同病灶。,different symptoms and signs that cant be explained by only one lesion.,诊断标准和分类标准,诊断标准和分类标准,脊髓型：,脱髓鞘过程有时仅限于脊髓，或虽然向中枢神经系统其他部位扩展但仅有脊髓部位的斑块产生症状。,MS of spinal cord type:,Demyelination in spinal cord only,sometimes it expand to other spaces of CNS,but only the lesion of spinal cord develop the symptoms.,诊断标准和分类标准,国外，例中，例（）有脊髓症状，中国例中有脊髓症状。,overseas,，,109(9%)of 1271MS have the symptoms of spinal cord;in China,70%of 256 have,the symptoms,特点：女性多；起病年龄大；慢性进展病程多；工作能力保存较好。,characteristics:usually seen in female,onset at old ages,chronic progression,and preserved more work capacity,.,诊断标准和分类标准,自然病程：,Natural progress,：,患者起病后呈进行性加重。,10,of patients have progressive exacerbation,约后期进入进行性加重。,about 2/3 of patients come into progressive,exacerbation phase.,.,为复发缓解型。,.,of patients are RRMS,临床分型,复发,-,缓解型,原发进展型,继发进展型,进展复发型,诊断标准和分类标准,实验室支持诊断,Supporting data of laboratory,组分区带或中枢神经系统中合成率增高。,IgG fraction bands or the Synthesis of IgG in CNS increased,血清中正常,normal level in serum,除外其他疾病：梅毒、亚急性硬化性全脑炎、肉芽肿病、胶原血管病等。,Exclude other diseases:syphilis,subacute sclerosis panencephalitis,granulomatosis,collagen vascular disorders,诊断标准和分类标准,临床确诊（,clinically definite,）,MS,2,次发作,又有,2,个不同病变部位的临床证据,Two episodes with clinical evidence of two different lesions,2,次发作，有一个部位病变的临床证据，和另一个部位病变的亚临床证据。,Two episodes with clinical evidence of one lesion and subclinical evidence of another one.,诊断标准和分类标准,临床很可能（,clinically probable,）,MS,2,次发作和,1,个部位病变的临床证据。,2,次发作必须累及,CNS,的不同部位。,two episodes with clinical evidence of one lesion must be attributable to involvement of 2 or more parts of CNS.,历史资料于此不能用作病变部位的临床证据。,History dates cant be the clinical ev