神經(jīng)肌接頭病重癥肌無力lamberteaton綜合征

1、神經(jīng)肌接頭病 (Disorders of neuromuscular transmission) 重癥肌無力 Lambert-Eaton 綜合征,Dep. of NeurologyThe 2nd Hospital Harbin Medical University,Neuromuscular Disorders Definition,The diseases of neuromus

2、cular junction (NMJ) describes a sets of disease caused by circulating factors such as neurotoxins or autoantibodies which bind with high affinity to specific proteins at the NMJ and disturb the neuromuscular transmissio

3、n.,Neuromusuclar Junction (NMJ) Physiology,the nerve AP reaches the nerve terminal which inflated and without myelin and leads to the opening of calcium channel and release of ACh into the synaptic cleft by exocytosi

4、s.,Neuromusuclar Junction (NMJ) Physiology,1/3 of the ACh diffuses rapidly to the postsynaptic membrane and binds to the AChRs, leading to opening of the AChR-associated cation channel and depolarization called the e

5、nd-plate potential (EPP). If the EPP exceeds certain threshold, voltage gated sodium channel at the postsynaptic membrane are opened. This generates the muscle action potential (CMAP) that propagates along the muscle f

6、iber and activates contraction.,Neuromusuclar Junction (NMJ) Physiology,Another 1/3 of the ACh is hydrolyzed by cholinesterase (ChE). The remaining 1/3 of the ACh is recaptured by the presynaptic membrane.,重癥肌無力 (My

7、asthenia Gravis, MG),概念病因及發(fā)病機(jī)制病理臨床表現(xiàn)診斷及鑒別診斷治療,Myasthenia gravis (MG)Definition,MG was originated from Latin, meaning very severe weakness. acquired MG is an antibody and complement-mediated, T cell-dependent autoi

8、mmune disease leading to a defect in neuromuscular transmission.,Myasthenia gravis ( MG) Epidemiology,It is the prototypic neuromuscular disorders with an incidence of 80-200 per million and prevalence about 500 per

9、million. In China, it is estimated that 0.6 million people were diagnosed as MG and most of them lives in the South of China. It had been a life-threatening disease before 1970’s, though nowadays the incidence of death

10、 has been greatly reduced to about 0.2%.,Myasthenia Gravis (MG)Etiology,The autoimmune origin of MG is proposed long before it was established in 1973 by the direct evidence provided by Patrick and Lindstrom, who have i

11、mmunized rabbit with affinity-purified Torpedo AChR with CFA and reproduced the animal models representing human MG (EAMG).The AChR is the autoantigen.,Myasthenia Gravis (MG)Etiology,The presence of anti-AChR Abs can b

12、e demonstrated in 80%-90% of MG patients. There is a 3:1 female-male ratio for patients who develop MG in early adult life. Overall, the above makes MG fulfills the criteria for autoimmune diseases.,Myasthenia Gravis (

13、MG)Etiology,Most of the patients with MG have abnormalities in the thymus, e.g. thymic hyperplastic or thymoma.Although the primary antiself event being unclear, thymus appears to be the place where it initiates.The g

14、eneral opinion is that virus infection or other nonspecific factors invades the thymus in genetically predisposed individuals leading to the development of MG.,Myasthenia Gravis (MG)Pathology,Lymphoid folliculus can be

15、seen in thymus. About 10% of MG patients has thymoma of epithelia type.Lymphorage, defined by aggregated lymphoid cells around the blood vessels, is sometimes seen in otherwise normal musculature in MG patients.,Myasthe

16、nia Gravis (MG)Pathology,At the NMJ, grossly simplified postsynaptic folds with deposition of immune-complex and the anti-AChR Abs is demonstrated by immunochemical studies. There is also considerable debris within the

17、widened synaptic cleft.Normal NMJ、NMJ in MG patients（示意圖）（電鏡）,Myasthenia Gravis (MG)Clinical Manifestations,MG can arise at any age, although young females and old males are more vulnerable to it. Precipitatin

18、g factors: concurrent infection, stress, weariness, menses, pregnancy or parturition. The disease initiates insidious and follows a slowly progressive course.,Myasthenia Gravis (MG)Clinical Manifestations,Clinically, M

19、G features with fluctuated muscular weakness in intensity during the day and easy fatigability.Typically, the weakness varies in distribution and severity from day to day.Characterized by abnormal weakness, which being

20、 worse at the end of the day or after exertion and tends to improve after rest or AChE treatment.,Myasthenia Gravis (MG)Clinical Manifestations,The weakness often begins with the lateral or bilateral extra-ocular muscle

21、s, leading to asymmetric ocular palsies (e.g. diplopia, strabismic) and ptosis.Pupillary responses are not affected.,Myasthenia Gravis (MG)Clinical Manifestations,The patients may present with less wrinkles, amimia, di

22、fficulty in closing the eyes or disclosing tooth;difficulty in chewing or swallowing, nasal speech;weakness of the neck or the proximal upper limbs.,Myasthenia Gravis (MG)Crisis—definition,Crisis describes a rapidly d

23、eveloped weakness in the bulbar muscles and respiratory insufficiency that necessitates assisted ventilation.It is the leading cause of death in patients with MG.,Myasthenia Gravis (MG)Crisis—classification,Myasthenic

24、crisis: able to react to AChE drugs and being hypersensitive to the curare.Cholinergic crisis: 1. overmedication can lead to increased weakness, which, unlike myasthenic weakness, is unaffected or

25、enhanced by intravenous edrophonium. 2. It may be accompanied by pallor, sweating, nausea, vomiting, salivation, colic, and diarrhea (muscarinic syndrome). Brittie crisis: unresponsive to AChE.,Myasthenia

26、Gravis (MG)Osserman Classification,Five subgroups can be defined among patients with myasthenia. I. Ocular IIa. Mild generalized IIb. Moderate generalized III. Progressively severe IV. late se

27、vere,Myasthenia Gravis (MG)Other classification,MG can also be subdivided into adolescent and adult type, neonatal MG, congenital myasthenia, D-Penicillamine induced myasthenia:

28、 a similar disorder in patients receiving penicillamine for rheumatoid arthritis frequently remits when the drug is discontinued.,Myasthenia Gravis (MG)Investigation,Routine examination on the blood, urea and CSF are no

29、rmal. X-rays and CT scans of the chest may reveal a coexisting thymoma in patients over 40 years.,Myasthenia Gravis (MG)Investigation,EMG: increased decrement (> 10%) of the evoked CMAP upon repeated stimuli at 3 or

30、 5 Hz.Single fiber myography shows reduced amplitude of MEPP and increased variability (jitter) or more blockade of impulses.,Myasthenia Gravis (MG)Investigation,The anti-AChR Abs present in 85-90% of patients with gen

31、eralized MG and in 50% of patients with ocular MG, but not present in healthy individuals.When the anti-AChR Abs are identified, the diagnosis is established.autoantibodies against striated muscles.,Myasthenia Gravis (

32、MG)Diagnosis,疲勞試驗(yàn)（Jolly試驗(yàn)）抗膽堿酯酶藥物試驗(yàn)1.騰喜龍（tensilon）試驗(yàn)2.新斯的明（neostigmine）試驗(yàn)重復(fù)神經(jīng)電刺激AChR抗體滴度測(cè)定：特征性意義,,,Myasthenia Gravis (MG) Diagnosis,edrophonium in 2-3 dose (totally 10mg) given i.v. give a rapid (within 2’) b

33、ut short-lived (less than 5’) improvement in strength in most patients with MG. neostigmine of 1.5mg given i.m. improves muscle strength within 30’ and lasts for 2 hs.false-positive and false-negative results can occur

34、.there is a small risk of cardiorespiratory collapse.,,Myasthenia Gravis (MG) Diagnosis,Once the diagnosis has been made, CT or MRI of the chest should be done to exclude an associated thymoma. Thyroid function an

35、d thyroid Abs should be measured, because of the increased frequency of thyroid disease.,Myasthenia Gravis (MG) Differential diagnosis,The differential diagnosis of MG is wide.Acquired MG v.s. congenital MG and  

36、 neurotoxins e.g. botulism, venoms.Ocular MG (of whom about 50% are AChR Ab-negative) v.s. ocular muscular dystrophy and mitochodrial cytopathy.Bulbar myasthenia v.s. brain stem stroke and motor-neuron disease (e.

37、g. ALS).,Myasthenia Gravis (MG)Differential diagnosis,patients with generalized weakness but are negative for AChR Abs v.s.＊neuropathies and myopathies ＊myasthenic syndromes (other disorders of the NMJ which

38、 neurophysiological studies might show changes similar to those of MG).,Myasthenia Gravis (MG) Treatment,AChE drugs provides symptomatic benefit without influencing the course of the underlying disease. pyridostigmin

39、e, at doses individually determined but usually between 60 and 180 mg q.q.d. Small doses of atropine may attenuate side effects such as diarrhea.,Myasthenia Gravis (MG) Treatment,thymectomy should be performed in pa

40、tients under 60 years of age. usually leads to symptomatic benefit or remissionHowever, its beneficial effect may not be evident immediately.,Myasthenia Gravis (MG) Treatment,corticosteriods are indicated for patien

41、ts who have responded poorly to AChE and have already under thymectomy. Treatments are initiated with the patient in hospital, since weakness may initially be exacerbated. An initial high dose of predinisone (60-80mg/d

42、 orally) can gradually be tapered to a relatively low maintenance level (10-20 mg/d) as improvement occurs.,Myasthenia Gravis (MG) Treatment,Immunosuppressant, e.g. azathioprine, is used as steriod-sparing agent. It

43、 can also be given in place of corticosteroids to patients who show no sustained benefit with low doses. The usual dose is 1-3 mg/kg/d, increased from a lower initial dose.,Myasthenia Gravis (MG) Treatment,plasmaphe

44、resis (PE) may be used during an acute exacerbation, myasthenic crisis, or under certain special circumstances, e.g. prior to surgery.intravenous immunoglobulins (IVIG) have been used to provide temporary benefit in cir

45、cumstances similar to those in which PE is used.,Myasthenia Gravis (MG) Treatment,Crisis: respiratory and bulbar complications require appropriate supportive measures, e.g. assisted ventilation and/or nasogastric fee

46、ding. PE and IVIG are needed.,Lambert-Eaton Syndrome (LEMS),概念病因及發(fā)病機(jī)制臨床表現(xiàn) 診斷及鑒別診斷治療,Lambert-Eaton Syndrome (LEMS) Definition,In the paraneoplastic disorder, Abs against tumor antigens cross-react with voltage-gat

47、ed calcium channels involved in acetylcholine release, leading to a disturbance of NMT.,Lambert-Eaton Syndrome (LEMS) Etiology,In 1957, Lambert and Eaton described a myasthenic syndrome that was electrophysiologically

48、distinct from MG. an archetypal paraneoplastic neurologic disorder, frequently associated with SCLC. occasionally associated with pernicious anemia.,Lambert-Eaton Syndrome (LEMS) Clinical Manifestations,LEMS is more c

49、ommon in males than females.Weakness involves predominantly proximal muscles of the limbs and nearly always affects the legs first. Strength may increase during the first few seconds of a voluntary contraction.,Lambert

50、-Eaton Syndrome (LEMS) Clinical Manifestations,Ocular syndromes are far less common than in MG. Weakness and fatigue of hip muscles with aching back and thigh muscles are common. Reflexes are absent. Autonomic disturb

51、ances, such as dry mouth, constipation, and impotence, may also occur.,Lambert-Eaton Syndrome (LEMS) Investigation,CMAP amplitude is decreased at low rates of repetitive nerve stimulation. the CMAP shows an increment

52、following high-frequency ( > 10 Hz) stimulation or a few seconds of voluntary contraction. The findings contrasted with those in MG.autoantibodies against the P/Q subtype of voltage-gated calcium channels (VGCC) is

53、 highly sensitive and specific.AChR-Ab (-).,Lambert-Eaton Syndrome (LEMS) Diagnosis and differential diagnosis,肌無力、腱反射減低、自主收縮后肌力增加。典型的電生理改變。通過檢測(cè)VGCC抗體加以驗(yàn)證(陽(yáng)性率>90%)。表17-1,Treatment,Therapy based on the etiology.P