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1、DemyelinatingDemyelinating disease of the CNS disease of the CNS 中枢神经系统脱髓鞘疾病中枢神经系统脱髓鞘疾病Tianjin medical University General hospitalTianjin medical University General hospitalZhou Zhou GuangGuang xi xi天津医科大学总医院神经内科天津医科大学总医院神经内科天津医科大学总医院神经内科天津医科大学总医院神经内科周广喜周广喜周广喜周广喜7702770277027702Overview Demyelinativ
2、e disease is a group of diseases of brain and spinal cord in which destruction of myelin is a prominent feature. Myelin sheaths play importance role in protecting and supporting for nervous fiber and transporting of material to neurons and maintaining of neurons ionic environment. The formation of m
3、yelin sheaths in both the central and peripheral nervous system follows a similar pattern. Central myelin is formed by an extension of membrane of the oligodendrocyte wrapping the axons, whereas peripheral myelin is formed by the extension of the Schwann cell membrane.The commonest accepted the path
4、ologic criteria of demyelinative disease in CNS:1. Destruction of the myelin sheaths of nerve 1. Destruction of the myelin sheaths of nerve fibers; fibers; 2. Relative sparing of other elements of nervous 2. Relative sparing of other elements of nervous tissue, i.e. of axis cylinders, nerve cell, an
5、d tissue, i.e. of axis cylinders, nerve cell, and supporting structure, and a relative lack of supporting structure, and a relative lack of WallerianWallerian, or secondary, degeneration off fiber , or secondary, degeneration off fiber tracts.tracts.3. A particular distribution of lesions often is 3
6、. A particular distribution of lesions often is perivenousperivenous and primarily in white matter. and primarily in white matter. Classification of demyelination disease in CNS DysmyelinativeDysmyelinative type ( type (leukodystrophyleukodystrophy) ) It It results results from from failure failure
7、to to form form normally normally constituted constituted myelin, myelin, due due to to genetic genetic enzymatic enzymatic disorders, disorders, such such as as adrenoleukodystrophyadrenoleukodystrophy (ADL), (ADL), GlobodGlobod leucodystrophyleucodystrophy ( (KrabbeKrabbe), ), MetachromaticMetachr
8、omatic leucodystrophyleucodystrophy (MLD (MLD) ) DemyelinatingDemyelinating type typeIt is breakdown of normally constituted myelin.It is breakdown of normally constituted myelin.Classifications of the demyelination diseaseMultiple sclerosisMultiple sclerosis1. 1. relapsing-remitting , RR relapsing-
9、remitting , RR 2. primary progressive, PP2. primary progressive, PP3. secondary progressive, SP3. secondary progressive, SP4. progressive relapsing , PR4. progressive relapsing , PRNeuromyelitisNeuromyelitis opticaoptica ( (DevicDevic) ) Diffuse Diffuse cerebral cerebral sclerosis sclerosis ( (Schil
10、derSchilder) ) & & concentric concentric sclerosis sclerosis of of BaloBalo Acute disseminated encephalomyelitis Acute disseminated encephalomyelitis Central Central pontinepontine myelinnolysismyelinnolysis Multiple sclerosis Multiple sclerosis is the most common demyelinating disorder. It is a dis
11、ease of the central white matter with “ lesions separated in time and space”. Generally, MS is characterized clinically by remitting - relapsing course. The disease usually occurs in young adults. The peak age of onset is 20-40 and 95% patients occurs between 10-60 years. More females than males are
12、 affected.Etiology and pathogenesisEtiology and pathogenesis1 1 1 1.Geographical influenceGeographical influenceGeographical influenceGeographical influence: : : : Populations Populations Populations Populations residing residing residing residing between between between between tropical tropical tr
13、opical tropical and and and and subtropical subtropical subtropical subtropical zones zones zones zones have have have have a a a a low low low low risk risk risk risk of of of of MS. MS. MS. MS. All All All All populations populations populations populations residing residing residing residing this
14、 this this this latitudes latitudes latitudes latitudes in in in in North North North North America and Europe are higher risk. America and Europe are higher risk. America and Europe are higher risk. America and Europe are higher risk. 2.2. Familial factors:Familial factors:Familial factors:Familial
15、 factors: It It It It was was was was found found found found that that that that almost almost almost almost 20% 20% 20% 20% of of of of index index index index cases cases cases cases had had had had an an an an affected affected affected affected relative, relative, relative, relative, again agai
16、n again again with with with with the the the the highest highest highest highest risk risk risk risk in in in in siblings siblings siblings siblings in in in in a a a a large large large large population population population population study study study study in in in in British. British. British.
17、 British. studies of twins studies of twins studies of twins studies of twins histocompatibilityhistocompatibilityhistocompatibilityhistocompatibility antigens antigens antigens antigens ( ( ( (HLAsHLAsHLAsHLAs) ) ) ) associations associations associations associations with HLA- A3, B7, B18, and Dw2
18、.with HLA- A3, B7, B18, and Dw2.with HLA- A3, B7, B18, and Dw2.with HLA- A3, B7, B18, and Dw2. Etiology and pathogenesisEtiology and pathogenesis3. 3. 3. 3. Infection and immunological mechanismInfection and immunological mechanismInfection and immunological mechanismInfection and immunological mech
19、anism: : immunoregulatory defects may play a critical role in immunoregulatory defects may play a critical role in immunoregulatory defects may play a critical role in immunoregulatory defects may play a critical role in pathophysiology.pathophysiology.pathophysiology.pathophysiology. autoimmunizati
20、on of T lymphocytes against myelin basic autoimmunization of T lymphocytes against myelin basic autoimmunization of T lymphocytes against myelin basic autoimmunization of T lymphocytes against myelin basic protein protein protein protein caused several different viruses.caused several different viru
21、ses.caused several different viruses.caused several different viruses. (Johanson)(Johanson)(Johanson)(Johanson) cellular cellular cellular cellular factors:factors:factors:factors: T T T T lymphocytes lymphocytes lymphocytes lymphocytes regulate regulate regulate regulate humoralhumoralhumoralhumora
22、l immune immune immune immune responses responses responses responses either either either either as as as as potentiatorspotentiatorspotentiatorspotentiators (T-helper (T-helper (T-helper (T-helper cells) cells) cells) cells) or or or or as as as as inhibitors inhibitors inhibitors inhibitors (T-su
23、ppressor (T-suppressor (T-suppressor (T-suppressor cells) cells) cells) cells) A A A A reduction reduction reduction reduction in in in in the the the the blood blood blood blood of of of of suppressor suppressor suppressor suppressor T T T T lymphocytes lymphocytes lymphocytes lymphocytes was was w
24、as was thought thought thought thought to to to to characterize characterize characterize characterize clinical clinical clinical clinical relapse, relapse, relapse, relapse, or or or or an an an an increase increase increase increase in in in in helper helper helper helper suppressor suppressor sup
25、pressor suppressor ratios, ratios, ratios, ratios, (CD4/CD8) (CD4/CD8) (CD4/CD8) (CD4/CD8) dose dose dose dose appear appear appear appear to to to to be be be be associated associated associated associated with with with with increasing disability in patients of MS.increasing disability in patients
26、 of MS.increasing disability in patients of MS.increasing disability in patients of MS. Raised Raised Raised Raised titrestitrestitrestitres to to to to many many many many common common common common virusesvirusesvirusesviruses have have have have been been been been found found found found in in
27、in in the the the the serum serum serum serum and and and and CSF CSF CSF CSF of of of of MS MS MS MS patients, patients, patients, patients, but but but but attempts attempts attempts attempts to to to to induce induce induce induce ms experimentally with viruses have been unsuccessful.ms experimen
28、tally with viruses have been unsuccessful.ms experimentally with viruses have been unsuccessful.ms experimentally with viruses have been unsuccessful.PathologyPathologyThe Area of demyelination are found in the white matter of the brain and spinal cord. The lesions may vary in diameter from less tha
29、n a millimeter to several centimeters. The periventricular localization is characteristic. Other favored structures are the optic nerves and chiasm, brainstem and cervical cord.There is myelin destruction with relative preservation of axons. An inflammatory infiltrate containing mononuclear cells an
30、d lymphocytes is found. Interstitial oedema occurs in acute lesions. Clinical featureEarly symptoms and signsEarly symptoms and signs1. 1.Weakness or numbness, sometimes both, in one or Weakness or numbness, sometimes both, in one or more limbs is the initial symptom in about half the more limbs is
31、the initial symptom in about half the patients. patients. 2. 2.Symptoms Symptoms of of tingling tingling of of the the extremities extremities and and tight tight band-band-like sensations around the trunk are commonly. like sensations around the trunk are commonly. 3. 3.Visual Visual involvement in
32、volvement most most commonly commonly takes takes the the form form of of an an acute acute optic optic neuritis neuritis with with ocular ocular pain. pain. Typically, Typically, there there is is a a central central scotomascotoma. . In In the the acute acute stages, stages, the the disc disc is i
33、s usually usually normal, normal, but but sometimes sometimes it it is is swollen swollen ( (papillitispapillitis) along with ) along with peripapillaryperipapillary haemorrhageshaemorrhages. . Early symptoms and signsEarly symptoms and signs4. 4.LhermitteLhermitte sign was frequent occurrence in MS
34、. sign was frequent occurrence in MS.5. 5.Dull, Dull, aching aching pain pain in in the the low low back back is is a a common common complaint. complaint. Sharp, Sharp, burning, burning, poorly poorly localized, localized, or or characteristic characteristic lancinating-radicularlancinating-radicul
35、ar pain, pain, localized localized to to limb limb or or discrete discrete part part of of the the trunk, trunk, occurs occurs but but is is infrequent. infrequent. 6. 6.Vertigo Vertigo and and diplopiadiplopia have have been been a a frequency frequency initial initial sign of brainstem involved in
36、 MS.sign of brainstem involved in MS.Other patterns of MS in progressive stage Other patterns of MS in progressive stage The clinical manifestation of MS is protean. The clinical manifestation of MS is protean. Brain stem involvement is common in MS. Brain stem involvement is common in MS. A A unila
37、teral unilateral or or bilateral bilateral internuclearinternuclear ophthalmoplegiaophthalmoplegia, , due due to to a a lesion lesion of of the the medial medial longitudinal longitudinal fasciculus, fasciculus, can can occur occur either either as as a a presenting feature, or in established cases
38、. presenting feature, or in established cases . Sixth Sixth nerve nerve palsies, palsies, conjugate conjugate gaze gaze paresis paresis and and the the one-and-a-half one-and-a-half syndrome syndrome are are also also seen. seen. Various Various disorders disorders of of vertical vertical gaze gaze
39、are are described. described. A A vertical vertical skew skew deviation deviation signifies signifies an an intrinsic intrinsic brain brain stem stem or or cerebellarcerebellar lesion lesion (Fig 12.15). (Fig 12.15). Other patterns of MS in progressive stageOther patterns of MS in progressive stage
40、Acute Acute myelitismyelitis (transverse (transverse myelitismyelitis) ) Motor symptomsMotor symptoms which which may may begin begin suddenly suddenly or or insidiously, insidiously, include include stiffness, stiffness, difficulty difficulty in in walking walking or or a a tendency tendency to to
41、trip. trip. Clinical Clinical findings findings include include depression depression of of the the abdominal abdominal reflexes, reflexes, lower lower limb limb spasticity spasticity and and extensor extensor plantar plantar responses. responses. Depression Depression of of limb limb reflexes refle
42、xes is is encountered encountered as as is is limb limb wasting, wasting, the the reflection reflection of of an an extensive extensive plaque plaque with with secondary secondary involvement involvement of of the the anterior horn or ventral root exit zoneanterior horn or ventral root exit zone Som
43、e patients do show this mental abnormalitySome patients do show this mental abnormality Symptoms of bladder dysfunctionSymptoms of bladder dysfunctionMain patterns of diseases progression for Main patterns of diseases progression for MSMS l l l l Relapsing Relapsing Relapsing Relapsing and and and a
44、nd remittingremittingremittingremitting with with with with lesions lesions lesions lesions often often often often occurring occurring occurring occurring in in in in different different different different parts parts parts parts of of of of the the the the CNS CNS CNS CNS at at at at different ti
45、mes.different times.different times.different times.l l l l Secondary Secondary Secondary Secondary progressiveprogressiveprogressiveprogressive when when when when the the the the disease disease disease disease starts starts starts starts with with with with a a a a relapsing relapsing relapsing r
46、elapsing remitting remitting remitting remitting picture, picture, picture, picture, but but but but recovery recovery recovery recovery from from from from each each each each successive successive successive successive relapse relapse relapse relapse becomes becomes becomes becomes less less less
47、less and and and and less less less less complete, complete, complete, complete, causing causing causing causing residual disability.residual disability.residual disability.residual disability.l l l l Primary Primary Primary Primary progressiveprogressiveprogressiveprogressive in in in in which whic
48、h which which there there there there is is is is little little little little or or or or no no no no recovery recovery recovery recovery from from from from relapses, relapses, relapses, relapses, with with with with a a a a cumulative cumulative cumulative cumulative disability.disability.disabili
49、ty.disability.Variant of MSNeuromyelitis optica ( Devic disease)Diffuse sclerosis or encephalitis periaxialis diffusa ( Schilder disease)Concentric sclerosis of BaloDevicDevic disease disease视神经脊髓炎（视神经脊髓炎（neuromyelitisneuromyelitis optica,NMOoptica,NMO）是一种主要累及视）是一种主要累及视神经和脊髓的中枢神经系统炎症脱髓鞘性疾病，又称神经和脊髓的中
50、枢神经系统炎症脱髓鞘性疾病，又称DevicDevic病或病或DevicDevic综合症，综合症，80%-90%80%-90%的病人可出现复发。的病人可出现复发。近年来临床、影像学、病理学和免疫学等研究证据提示近年来临床、影像学、病理学和免疫学等研究证据提示NMONMO是不同是不同于多发性硬化的一类具有独特免疫病理学机制及临床特征的自身于多发性硬化的一类具有独特免疫病理学机制及临床特征的自身免疫性疾病免疫性疾病 20042004年，年，LennonLennon等人通过间接免疫荧光法检测到等人通过间接免疫荧光法检测到NMONMO病人血清中存病人血清中存在一种特异性自身抗体在一种特异性自身抗体NMO
51、-NMO-IgGIgG，其特异性结合到水通道蛋白，其特异性结合到水通道蛋白4 4（aquaporin-4,AQP4aquaporin-4,AQP4），与），与AQP-4AQP-4发生免疫应答，导致血脑屏障发生免疫应答，导致血脑屏障功能的障碍功能的障碍22。其病理学表现为累及脊髓白质和灰质的病灶，受累脊髓肿胀、软其病理学表现为累及脊髓白质和灰质的病灶，受累脊髓肿胀、软化，出现广泛的脱髓鞘，并有空洞、坏死以及急性轴索损害；典化，出现广泛的脱髓鞘，并有空洞、坏死以及急性轴索损害；典型病灶位于脊髓中央，少突胶质细胞丢失明显较少髓鞘再生型病灶位于脊髓中央，少突胶质细胞丢失明显较少髓鞘再生 The dif
52、ferent between NMO and MSThe different between NMO and MS 临床上比较临床上比较MSMS病变主要在大脑的脑室周围，临床的复发率要低于病变主要在大脑的脑室周围，临床的复发率要低于NMONMO，视神经和脊髓损害的几率少，即使损害到脊髓也较轻。，视神经和脊髓损害的几率少，即使损害到脊髓也较轻。影像学的区别非常重要：影像学的区别非常重要：MSMS脑内病灶多见，病灶数量较多，形态学上多数呈现卵圆形、圆脑内病灶多见，病灶数量较多，形态学上多数呈现卵圆形、圆形或垂直朝向脑室的病灶，脊髓形或垂直朝向脑室的病灶，脊髓MRIMRI病灶较小，多局限在一个脊椎病
53、灶较小，多局限在一个脊椎节段，轴位上显示病灶局限，多位于脊髓髓内偏外侧；节段，轴位上显示病灶局限，多位于脊髓髓内偏外侧；NMONMO也可出现颅内病灶，但相对不典型，多累及皮层下白质、胼胝也可出现颅内病灶，但相对不典型，多累及皮层下白质、胼胝体、脑干及下丘脑等部位，这些病灶数量较少，呈现大片状不规体、脑干及下丘脑等部位，这些病灶数量较少，呈现大片状不规整形状，脊髓病灶较大，其长度多大于三个脊椎节段，位于脊髓整形状，脊髓病灶较大，其长度多大于三个脊椎节段，位于脊髓中央位置。中央位置。NMONMO患者患者CSFCSF水通道蛋白水通道蛋白4 4抗体阳性抗体阳性 。 Concentric scleros
54、is of Concentric sclerosis of BaloBaloLaboratory findingsLaboratory findings CSF:CSF:CSF:CSF: mononuclear mononuclear mononuclear mononuclear pleocytosispleocytosispleocytosispleocytosis ( usually 50 cells /cm). ( usually 50 cells /cm). ( usually 50 cells /cm). ( usually 50 cells /cm). protein conte
55、nt is increased slightly. protein content is increased slightly. protein content is increased slightly. protein content is increased slightly. IgGIgGIgGIgG is increased. is increased. is increased. is increased. OligoclonalOligoclonalOligoclonalOligoclonal bands (OB )is found bands (OB )is found ban
56、ds (OB )is found bands (OB )is found Evoked Evoked Evoked Evoked potentials potentials potentials potentials abnormal:abnormal:abnormal:abnormal: these these these these include include include include visual, visual, visual, visual, auditory auditory auditory auditory and and and and somatosensorys
57、omatosensorysomatosensorysomatosensory evoked responses. evoked responses. evoked responses. evoked responses.CT scanning can demonstrate abnormalities single .CT scanning can demonstrate abnormalities single .CT scanning can demonstrate abnormalities single .CT scanning can demonstrate abnormalitie
58、s single .MRI MRI MRI MRI has has has has proved proved proved proved of of of of immense immense immense immense valuevaluevaluevalue T2-weighted T2-weighted T2-weighted T2-weighted images images images images are are are are particularly particularly particularly particularly useful useful useful
59、useful for for for for demonstrating demonstrating demonstrating demonstrating lesions lesions lesions lesions in in in in the the the the periventricularperiventricularperiventricularperiventricular region. region. region. region. The The The The technique technique technique technique allows allow
60、s allows allows demonstration demonstration demonstration demonstration of of of of lesions lesions lesions lesions of of of of the the the the brain brain brain brain stem stem stem stem and and and and in in in in the the the the spinal spinal spinal spinal cord. cord. cord. cord. enhancement enha
61、ncement enhancement enhancement has has has has been been been been used used used used to to to to assess assess assess assess the the the the activity of any abnormal signal area. activity of any abnormal signal area. activity of any abnormal signal area. activity of any abnormal signal area. Diag
62、nosis (Poser 1983) Diagnosis (Poser 1983) NMSS诊断标准 (2001)Differential diagnosisDifferential diagnosis1.1.1.1.Acute Acute Acute Acute disseminated disseminated disseminated disseminated encephalomyelitisencephalomyelitisencephalomyelitisencephalomyelitis, , , , (ADEM)(ADEM)(ADEM)(ADEM) It It It It is
63、 is is is an an an an acute acute acute acute illness illness illness illness with with with with scattered scattered scattered scattered small small small small demyelinativedemyelinativedemyelinativedemyelinative lesions, lesions, lesions, lesions, but but but but it it it it is is is is self-limi
64、ted self-limited self-limited self-limited and and and and monophasicmonophasicmonophasicmonophasic. . . . Pathologically, Pathologically, Pathologically, Pathologically, perivascularperivascularperivascularperivascular areas areas areas areas of of of of demyelinationdemyelinationdemyelinationdemye
65、lination are are are are scattered scattered scattered scattered throughout throughout throughout throughout the the the the brain brain brain brain and and and and spinal spinal spinal spinal cord, cord, cord, cord, with with with with an an an an associated associated associated associated inflamm
66、atory inflammatory inflammatory inflammatory reaction. reaction. reaction. reaction. A A A A similar similar similar similar disorder disorder disorder disorder may may may may also also also also occur occur occur occur independently, independently, independently, independently, with with with with
67、 no no no no apparent apparent apparent apparent infection; infection; infection; infection; it it it it may may may may then then then then represent represent represent represent the the the the initial initial initial initial manifestation manifestation manifestation manifestation of of of of mul
68、tiple multiple multiple multiple sclerosis. sclerosis. sclerosis. sclerosis. Furthermore, Furthermore, Furthermore, Furthermore, fever, fever, fever, fever, stupor, stupor, stupor, stupor, and and and and coma, coma, coma, coma, which which which which are are are are characteristic, rarely occur in
69、 MS.characteristic, rarely occur in MS.characteristic, rarely occur in MS.characteristic, rarely occur in MS.Differential diagnosisDifferential diagnosis2. 2.systemic systemic lupus lupus erythematosuserythematosus and and other other autoimmune autoimmune diseasedisease. . there there may may be be
70、 multiple multiple lesions lesions of of CNS CNS white white matter. matter. Close Close attention attention to to the the characteristic characteristic history history (rash (rash and and arthritis arthritis etc.) etc.) and and serologic serologic findings findings should should permit permit the t
71、he distinction of the two diseases.distinction of the two diseases.3. 3. Cervical Cervical spondylosisspondylosis The typical protein abnormalities of The typical protein abnormalities of MS is absent. The disturbance of bladder function occur MS is absent. The disturbance of bladder function occur
72、late or not at all in it. late or not at all in it. 4. 4. BehcetBehcet disease disease are recurrent are recurrent iridocyclitisiridocyclitis and meningitis , and meningitis , mucous membrane ulcer of mouth and genitalia , and mucous membrane ulcer of mouth and genitalia , and symptoms of symptoms o
73、f articulararticular. renal, lung and multifocal cerebral . renal, lung and multifocal cerebral disease. disease. TreatmentTreatmentTreatmentTreatment1. 1.Corticosteroids:Corticosteroids: MethylprednisoloneMethylprednisolone is is 500 500 to to 1000 1000 mg mg daily daily for for 3-5 3-5 days, days,
74、 iv., iv., followed followed by by high high oral oral doses doses of of prednisonprednison 60 60 mg mg daily daily and and tapering tapering this this dosage dosage over over a a 12 12 day day is is generally generally effective effective and and 5-5-10/week.10/week.2.2.Immune globulinImmune globul
75、in (IG) iv 0.4/kg /d 3-5 days. (IG) iv 0.4/kg /d 3-5 days.3. 3.Beta-Interferon Beta-Interferon 1-a 1-a and and 1-b:1-b: (30ug (30ug or or 6.6 6.6 million million unit unit imim/weekly) /weekly) and and Copolymer 1Copolymer 1 ( (GlatiramerGlatiramer acetate) (20mg/daily, subcutaneous) acetate) (20mg/
76、daily, subcutaneous)4. 4.Suppression Suppression of of the the immune immune system:system: AzathioprineAzathioprine or or cyclophosphamidecyclophosphamide . .5.5.PlasmapheresisPlasmapheresis6. 6.Symptomatic Symptomatic treatment:treatment: spasticity spasticity BaclofenBaclofen; ; painful painful TegretalTegretal ; ; Intention tremor Intention tremor ClonazepamClonazepam; tiredness ; tiredness AmantadineAmantadine 问答题问答题简述脑炎主要临床表现（脑炎的共性表现）？简述脑炎主要临床表现（脑炎的共性表现）？中枢神经系统脱髓鞘疾病的药物治疗？中枢神经系统脱髓鞘疾病的药物治疗？
