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1、神经肌接头病 (Disorders of neuromuscular transmission) 重症肌无力 Lambert-Eaton 综合征,Dep. of NeurologyThe 2nd Hospital Harbin Medical University,神经肌接头病 (Disorders of neuromusc,Neuromuscular Disorders Definition,The diseases of neuromuscular junction (NMJ) describes a sets of disease caused by circulating factor
2、s such as neurotoxins or autoantibodies which bind with high affinity to specific proteins at the NMJ and disturb the neuromuscular transmission.,Neuromuscular Disorders,Neuromusuclar Junction (NMJ) Physiology,the nerve AP reaches the nerve terminal which inflated and without myelin and leads to the
3、 opening of calcium channel and release of ACh into the synaptic cleft by exocytosis.,Neuromusuclar Junction (NMJ),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
4、 depolarization called the end-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 fiber and activates contraction.,Neuromusuclar Junction
5、 (NMJ),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.,Neuromusuclar Junction (NMJ),重症肌无力 (Myasthenia Gravis, MG),概念病因及发病机制病理临床表现诊断及鉴别诊断治疗,重症肌无力 (Myasthenia Gravis, MG)概,Myas
6、thenia gravis (MG)Definition,MG was originated from Latin, meaning very severe weakness. acquired MG is an antibody and complement-mediated, T cell-dependent autoimmune disease leading to a defect in neuromuscular transmission.,Myasthenia gravis (MG)Definit,Myasthenia gravis ( MG) Epidemiology,It is
7、 the prototypic neuromuscular disorders with an incidence of 80-200 per million and prevalence about 500 per 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 1970s, though nowad
8、ays the incidence of death has been greatly reduced to about 0.2%.,Myasthenia gravis ( MG) Ep,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 immunized rabbit with affinit
9、y-purified Torpedo AChR with CFA and reproduced the animal models representing human MG (EAMG).The AChR is the autoantigen.,Myasthenia Gravis (MG)Etiolog,Myasthenia Gravis (MG)Etiology,The presence of anti-AChR Abs can be demonstrated in 80%-90% of MG patients. There is a 3:1 female-male ratio for p
10、atients who develop MG in early adult life. Overall, the above makes MG fulfills the criteria for autoimmune diseases.,Myasthenia Gravis (MG)Etiolog,Myasthenia Gravis (MG)Etiology,Most of the patients with MG have abnormalities in the thymus, e.g. thymic hyperplastic or thymoma.Although the primary
11、antiself event being unclear, thymus appears to be the place where it initiates.The general 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)Etiolog,Myasthenia Gravis (MG)Pat
12、hology,Lymphoid folliculus can be 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.,Myasthenia Gravis (MG)Patholo,Myasthenia Gravis (MG)Pa
13、thology,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 widened synaptic cleft.Normal NMJ、NMJ in MG patients（示意图）（电镜）,Myasthenia Gravis (MG)Patholo,Myasth
14、enia Gravis (MG)Clinical Manifestations,MG can arise at any age, although young females and old males are more vulnerable to it. Precipitating factors: concurrent infection, stress, weariness, menses, pregnancy or parturition. The disease initiates insidious and follows a slowly progressive course.,
15、Myasthenia Gravis (MG)Clinica,Myasthenia Gravis (MG)Clinical Manifestations,Clinically, MG 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, whic
16、h being worse at the end of the day or after exertion and tends to improve after rest or AChE treatment.,Myasthenia Gravis (MG)Clinica,Myasthenia Gravis (MG)Clinical Manifestations,The weakness often begins with the lateral or bilateral extra-ocular muscles, leading to asymmetric ocular palsies (e.g
17、. diplopia, strabismic) and ptosis.Pupillary responses are not affected.,Myasthenia Gravis (MG)Clinica,Myasthenia Gravis (MG)Clinical Manifestations,The patients may present with less wrinkles, amimia, difficulty in closing the eyes or disclosing tooth;difficulty in chewing or swallowing, nasal spee
18、ch;weakness of the neck or the proximal upper limbs.,Myasthenia Gravis (MG)Clinica,Myasthenia Gravis (MG)Crisisdefinition,Crisis describes a rapidly developed weakness in the bulbar muscles and respiratory insufficiency that necessitates assisted ventilation.It is the leading cause of death in patie
19、nts with MG.,Myasthenia Gravis (MG)Crisis,Myasthenia Gravis (MG)Crisisclassification,Myasthenic 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 enhance
20、d 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 Gravis (MG)Crisis,Myasthenia Gravis (MG)Osserman Classification,Five subgroups can be defined among pa
21、tients with myasthenia. I.Ocular IIa. Mild generalized IIb. Moderate generalized III. Progressively severe IV. late severe,Myasthenia Gravis (MG)Osserma,Myasthenia Gravis (MG)Other classification,MG can also be subdivided into adolescent and adult type, neonatal MG, congenital myasthenia, D-Penicill
22、amine induced myasthenia: a similar disorder in patients receiving penicillamine for rheumatoid arthritis frequently remits when the drug is discontinued.,Myasthenia Gravis (MG)Other c,Myasthenia Gravis (MG)Investigation,Routine examination on the blood, urea and CSF are normal. X-rays and CT scans
23、of the chest may reveal a coexisting thymoma in patients over 40 years.,Myasthenia Gravis (MG)Investi,Myasthenia Gravis (MG)Investigation,EMG: increased decrement ( 10%) of the evoked CMAP upon repeated stimuli at 3 or 5 Hz.Single fiber myography shows reduced amplitude of MEPP and increased variabi
24、lity (jitter) or more blockade of impulses.,Myasthenia Gravis (MG)Investi,Myasthenia Gravis (MG)Investigation,The anti-AChR Abs present in 85-90% of patients with generalized MG and in 50% of patients with ocular MG, but not present in healthy individuals.When the anti-AChR Abs are identified, the d
25、iagnosis is established.autoantibodies against striated muscles.,Myasthenia Gravis (MG)Investi,Myasthenia Gravis (MG)Diagnosis,疲劳试验（Jolly试验）抗胆碱酯酶药物试验1.腾喜龙（tensilon）试验2.新斯的明（neostigmine）试验重复神经电刺激AChR抗体滴度测定：特征性意义,Myasthenia Gravis (MG)Diagnos,Myasthenia Gravis (MG) Diagnosis,edrophonium in 2-3 dose (t
26、otally 10mg) given i.v. give a rapid (within 2) but 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.there is a small risk of cardiores
27、piratory collapse.,Myasthenia Gravis (MG) D,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 and thyroid Abs should be measured, because of the increased frequency of thyroid disease.,Myastheni
28、a Gravis (MG) Di,Myasthenia Gravis (MG) Differential diagnosis,The differential diagnosis of MG is wide.Acquired MG v.s. congenital MG and 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
29、v.s. brain stem stroke and motor-neuron disease (e.g. ALS).,Myasthenia Gravis (MG) Diffe,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 neurophysiolog
30、ical studies might show changes similar to those of MG).,Myasthenia Gravis (MG)Differe,Myasthenia Gravis (MG) Treatment,AChE drugs provides symptomatic benefit without influencing the course of the underlying disease. pyridostigmine, at doses individually determined but usually between 60 and 180 mg
31、 q.q.d. Small doses of atropine may attenuate side effects such as diarrhea.,Myasthenia Gravis (MG) Trea,Myasthenia Gravis (MG) Treatment,thymectomy should be performed in patients under 60 years of age. usually leads to symptomatic benefit or remissionHowever, its beneficial effect may not be evide
32、nt immediately.,Myasthenia Gravis (MG) Tre,Myasthenia Gravis (MG) Treatment,corticosteriods are indicated for patients 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 h
33、igh dose of predinisone (60-80mg/d orally) can gradually be tapered to a relatively low maintenance level (10-20 mg/d) as improvement occurs.,Myasthenia Gravis (MG) Trea,Myasthenia Gravis (MG) Treatment,Immunosuppressant, e.g. azathioprine, is used as steriod-sparing agent. It can also be given in p
34、lace 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) Tre,Myasthenia Gravis (MG) Treatment,plasmapheresis (PE) may be used during an acute exacerbation, myasthenic crisis, or under
35、certain special circumstances, e.g. prior to surgery.intravenous immunoglobulins (IVIG) have been used to provide temporary benefit in circumstances similar to those in which PE is used.,Myasthenia Gravis (MG) Tre,Myasthenia Gravis (MG) Treatment,Crisis: respiratory and bulbar complications require
36、appropriate supportive measures, e.g. assisted ventilation and/or nasogastric feeding. PE and IVIG are needed.,Myasthenia Gravis (MG) Tre,Lambert-Eaton Syndrome (LEMS),概念病因及发病机制临床表现 诊断及鉴别诊断治疗,Lambert-Eaton Syndrome (LEMS),Lambert-Eaton Syndrome (LEMS) Definition,In the paraneoplastic disorder, Abs a
37、gainst tumor antigens cross-react with voltage-gated calcium channels involved in acetylcholine release, leading to a disturbance of NMT.,Lambert-Eaton Syndrome (LEMS),Lambert-Eaton Syndrome (LEMS) Etiology,In 1957, Lambert and Eaton described a myasthenic syndrome that was electrophysiologically di
38、stinct from MG. an archetypal paraneoplastic neurologic disorder, frequently associated with SCLC. occasionally associated with pernicious anemia.,Lambert-Eaton Syndrome (LEMS),Lambert-Eaton Syndrome (LEMS) Clinical Manifestations,LEMS is more common in males than females.Weakness involves predomina
39、ntly 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-Eaton Syndrome (LEMS),Lambert-Eaton Syndrome (LEMS) Clinical Manifestations,Ocular syndromes are far less common than in MG. Weakness an
40、d fatigue of hip muscles with aching back and thigh muscles are common. Reflexes are absent. Autonomic disturbances, such as dry mouth, constipation, and impotence, may also occur.,Lambert-Eaton Syndrome (LEMS),Lambert-Eaton Syndrome (LEMS) Investigation,CMAP amplitude is decreased at low rates of r
41、epetitive nerve stimulation. the CMAP shows an increment 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 highly sensitive and specific.
42、AChR-Ab (-).,Lambert-Eaton Syndrome (LEMS),Lambert-Eaton Syndrome (LEMS) Diagnosis and differential diagnosis,肌无力、腱反射减低、自主收缩后肌力增加。典型的电生理改变。通过检测VGCC抗体加以验证(阳性率90%)。表17-1,Lambert-Eaton Syndrome (LEMS),Treatment,Therapy based on the etiology.PE.IVIG.,TreatmentTherapy based on the,本课重点,MG的临床表现 肌肉病态疲劳，晨轻暮重MG危象的概念及分型MG的诊断MG和LEMS的鉴别,本课重点MG的临床表现,
