1. 神经肌接头病 (Disorders of neuromuscular transmission) 重症肌无力 Lambert-Eaton 综合征 Dep. of Neurology The 2nd Hospital Harbin Medical University

2. Neuromuscular Disorders D efinition The diseases of neuromuscular 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 transmission.

3. 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 exocytosis.

4. 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 end-plate potential (EPP).AChR 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.

5. 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.

6. 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

7. Myasthenia gravis (MG) D efinition 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.

8. Myasthenia gravis ( MG) E pidemiology It is 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 1970’s, though nowadays the incidence of death has been greatly reduced to about 0.2%.

9. Myasthenia Gravis (MG) E tiology 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 affinity-purified Torpedo AChR with CFA and reproduced the animal models representing human MG (EAMG). The AChR is the autoantigen.

10. Myasthenia Gravis (MG) E tiology The presence of anti-AChR Abs can be 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.

11. Myasthenia Gravis (MG) E tiology 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 general opinion is that virus infection or other nonspecific factors invades the thymus in genetically predisposed individuals leading to the development of MG.

12. Myasthenia Gravis (MG) P athology 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.

13. Myasthenia Gravis (MG) P athology 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.NMJ Normal NMJ 、 NMJ in MG patients （示意图）示意图 （电镜）电镜

14. Myasthenia Gravis (MG) C linical 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) C linical 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, which being worse at the end of the day or after exertion and tends to improve after rest or AChE treatment.

16. Myasthenia Gravis (MG) C linical Manifestations The weakness often begins with the lateral or bilateral extra-ocular muscles, leading to asymmetric ocular palsies (e.g. diplopia, strabismic) and ptosis. Pupillary responses are not affected.

17. Myasthenia Gravis (MG) C linical Manifestations The patients may present with less wrinkles, amimia, difficulty in closing the eyes or disclosing tooth; difficulty in chewing or swallowing, nasal speech; weakness of the neck or the proximal upper limbs.

18. Myasthenia Gravis (MG) C risis—definition 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 patients with MG.

19. Myasthenia Gravis (MG) C risis—classification 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 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.

20. Myasthenia Gravis (MG) O sserman Classification Five subgroups can be defined among patients with myasthenia. I. Ocular IIa. Mild generalized IIb. Moderate generalized III. Progressively severe IV. late severe

21. Myasthenia Gravis (MG) O ther classification MG can also be subdivided into adolescent and adult type, neonatal MG, congenital myasthenia, D-Penicillamine induced myasthenia: a similar disorder in patients receiving penicillamine for rheumatoid arthritis frequently remits when the drug is discontinued.

22. Myasthenia Gravis (MG) I nvestigation Routine examination on the blood, urea and CSF are normal. X-rays and CT scans of the chest may reveal a coexisting thymoma in patients over 40 years.CT

23. Myasthenia Gravis (MG) I nvestigation EMG: increased decrement (> 10%) of the evoked CMAP upon repeated stimuli at 3 or 5 Hz. EMG Single fiber myography shows reduced amplitude of MEPP and increased variability (jitter) or more blockade of impulses.

24. Myasthenia Gravis (MG) I nvestigation 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 diagnosis is established. autoantibodies against striated muscles.

25. Myasthenia Gravis (MG) D iagnosis 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

26. Myasthenia Gravis (MG) D iagnosis edrophonium in 2-3 dose (totally 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 cardiorespiratory collapse.

27. Myasthenia Gravis (MG) D iagnosis 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.

28. Myasthenia Gravis (MG) D ifferential 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 v.s. brain stem stroke and motor-neuron disease (e.g. ALS).

29. Myasthenia Gravis (MG) D ifferential diagnosis patients with generalized weakness but are negative for AChR Abs v.s. ＊ neuropathies and myopathies ＊ myasthenic syndromes (other disorders of the NMJ which neurophysiological studies might show changes similar to those of MG).

30. Myasthenia Gravis (MG) T reatment 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 q.q.d. Small doses of atropine may attenuate side effects such as diarrhea.

31. Myasthenia Gravis (MG) T reatment thymectomy should be performed in patients under 60 years of age. usually leads to symptomatic benefit or remission However, its beneficial effect may not be evident immediately.

32. Myasthenia Gravis (MG) T reatment 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 high dose of predinisone (60- 80mg/d orally) can gradually be tapered to a relatively low maintenance level (10-20 mg/d) as improvement occurs.

33. Myasthenia Gravis (MG) T reatment Immunosuppressant, e.g. azathioprine, is used as steriod-sparing agent. It 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.

34. Myasthenia Gravis (MG) T reatment plasmapheresis (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 circumstances similar to those in which PE is used.

35. Myasthenia Gravis (MG) T reatment Crisis: respiratory and bulbar complications require appropriate supportive measures, e.g. assisted ventilation and/or nasogastric feeding. PE and IVIG are needed.

36. 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

37. Lambert-Eaton Syndrome (LEMS) D efinition In the paraneoplastic disorder, Abs against tumor antigens cross-react with voltage- gated calcium channels involved in acetylcholine release, leading to a disturbance of NMT.

38. Lambert-Eaton Syndrome (LEMS) Etiology In 1957, Lambert and Eaton described a myasthenic syndrome that was electrophysiologically distinct from MG. an archetypal paraneoplastic neurologic disorder, frequently associated with SCLC. occasionally associated with pernicious anemia.

39. Lambert-Eaton Syndrome (LEMS) C linical Manifestations LEMS is more common 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.

40. Lambert-Eaton Syndrome (LEMS) C linical 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 disturbances, such as dry mouth, constipation, and impotence, may also occur.

41. Lambert-Eaton Syndrome (LEMS) I nvestigation CMAP amplitude is decreased at low rates of repetitive 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. AChR-Ab (-).

42. Lambert-Eaton Syndrome (LEMS) D iagnosis 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 表 17-1

43. Treatment Therapy based on the etiology. PE. IVIG.

44. 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