神经肌接头病重症肌无力lamberteaton综合征

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 Neuromuscular Disorders Definition 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. Neuromusuclar Junction (NMJ) Physiology nthe 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. Neuromusuclar Junction (NMJ) Physiology n1/3 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). nIf the EPP exceeds certain threshold, voltage gated sodium channel at the postsynaptic membrane are opened. nThis generates the muscle action potential (CMAP) that propagates along the muscle fiber and activates contraction. Neuromusuclar Junction (NMJ) Physiology nAnother 1/3 of the ACh is hydrolyzed by cholinesterase (ChE). nThe remaining 1/3 of the ACh is recaptured by the presynaptic membrane. 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 Myasthenia gravis (MG) Definition nMG was originated from Latin, meaning very severe weakness. nacquired MG is an antibody and complement -mediated, T cell-dependent autoimmune disease leading to a defect in neuromuscular transmission. Myasthenia gravis ( MG) Epidemiology nIt is the prototypic neuromuscular disorders with an incidence of 80-200 per million and prevalence about 500 per million. nIn China, it is estimated that 0.6 million people were diagnosed as MG and most of them lives in the South of China. nIt had been a life-threatening disease before 1970s, though nowadays the incidence of death has been greatly reduced to about 0.2%. Myasthenia Gravis (MG) Etiology nThe 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). nThe AChR is the autoantigen. Myasthenia Gravis (MG) Etiology nThe presence of anti-AChR Abs can be demonstrated in 80%-90% of MG patients. nThere is a 3:1 female-male ratio for patients who develop MG in early adult life. nOverall, the above makes MG fulfills the criteria for autoimmune diseases. Myasthenia Gravis (MG) Etiology nMost of the patients with MG have abnormalities in the thymus, e.g. thymic hyperplastic or thymoma. nAlthough the primary antiself event being unclear, thymus appears to be the place where it initiates. nThe 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) Pathology nLymphoid folliculus can be seen in thymus. About 10% of MG patients has thymoma of epithelia type. nLymphorage, defined by aggregated lymphoid cells around the blood vessels, is sometimes seen in otherwise normal musculature in MG patients. Myasthenia Gravis (MG) Pathology nAt 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) Clinical Manifestations nMG can arise at any age, although young females and old males are more vulnerable to it. nPrecipitating factors: concurrent infection, stress, weariness, menses, pregnancy or parturition. nThe disease initiates insidious and follows a slowly progressive course. Myasthenia Gravis (MG) Clinical Manifestations nClinically, MG features with fluctuated muscular weakness in intensity during the day and easy fatigability. nTypically, the weakness varies in distribution and severity from day to day. nCharacterized by abnormal weakness, which being worse at the end of the day or after exertion and tends to improve after rest or AChE treatment. Myasthenia Gravis (MG) Clinical Manifestations nThe weakness often begins with the lateral or bilateral extra-ocular muscles, leading to asymmetric ocular palsies (e.g. diplopia, strabismic) and ptosis. nPupillary responses are not affected. Myasthenia Gravis (MG) Clinical Manifestations nThe patients may present with less wrinkles, amimia, difficulty in closing the eyes or disclosing tooth; ndifficulty in chewing or swallowing, nasal speech; nweakness of the neck or the proximal upper limbs. Myasthenia Gravis (MG) Crisisdefinition nCrisis describes a rapidly developed weakness in the bulbar muscles and respiratory insufficiency that necessitates assisted ventilation. nIt is the leading cause of death in patients with MG. Myasthenia Gravis (MG) Crisisclassification nMyasthenic crisis: able to react to AChE drugs and being hypersensitive to the curare. nCholinergic 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). nBrittie crisis: unresponsive to AChE. Myasthenia Gravis (MG) Osserman Classification nFive subgroups can be defined among patients with myasthenia. I. Ocular IIa. Mild generalized IIb. Moderate generalized III. Progressively severe IV. late severe Myasthenia Gravis (MG) Other classification nMG 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. Myasthenia Gravis (MG) Investigation nRoutine examination on the blood, urea and CSF are normal. nX-rays and CT scans of the chest may reveal a coexisting thymoma in patients over 40 years. Myasthenia Gravis (MG) Investigation nEMG: increased decrement ( 10%) of the evoked CMAP upon repeated stimuli at 3 or 5 Hz. nSingle fiber myography shows reduced amplitude of MEPP and increased variability (jitter) or more blockade of impulses. Myasthenia Gravis (MG) Investigation nThe 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. nWhen the anti-AChR Abs are identified, the diagnosis is established. nautoantibodies against striated muscles. Myasthenia Gravis (MG) Diagnosis n疲劳试验（Jolly试验） n抗胆碱酯酶药物试验 1.腾喜龙（tensilon）试验 2.新斯的明（neostigmine）试验 n重复神经电刺激 nAChR抗体滴度测定：特征性意义 Myasthenia Gravis (MG) Diagnosis nedrophonium 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. nneostigmine of 1.5mg given i.m. improves muscle strength within 30 and lasts for 2 hs. nfalse-positive and false-negative results can occur. nthere is a small risk of cardiorespiratory collapse. Myasthenia Gravis (MG) Diagnosis nOnce the diagnosis has been made, CT or MRI of the chest should be done to exclude an associated thymoma. nThyroid function and 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. nAcquired MG v.s. congenital MG and neurotoxins e.g. botulism, venoms. nOcular MG (of whom about 50% are AChR Ab-negative) v.s. ocular muscular dystrophy and mitochodrial cytopathy. nBulbar myasthenia v.s. brain stem stroke and motor-neuron disease (e.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 neurophysiological studies might show changes similar to those of MG). Myasthenia Gravis (MG) Treatment nAChE drugs provides symptomatic benefit without influencing the course of the underlying disease. npyridostigmine, at doses individually determined but usually between 60 and 180 mg q.q.d. nSmall doses of atropine may attenuate side effects such as diarrhea. Myasthenia Gravis (MG) Treatment nthymectomy should be performed in patients under 60 years of age. nusually leads to symptomatic benefit or remission nHowever, its beneficial effect may not be evident immediately. Myasthenia Gravis (MG) Treatment ncorticosteriods are indicated for patients who have responded poorly to AChE and have already under thymectomy. nTreatments are initiated with the patient in hospital, since weakness may initially be exacerbated. nAn 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. Myasthenia Gravis (MG) Treatment nImmunosuppressant, e.g. azathioprine, is used as steriod-sparing agent. nIt can also be given in place of corticosteroids to patients who show no sustained benefit with low doses. nThe usual dose is 1-3 mg/kg/d, increased from a lower initial dose. Myasthenia Gravis (MG) Treatment nplasmapheresis (PE) may be used during an acute exacerbation, myasthenic crisis, or under certain special circumstances, e.g. prior to surgery. nintravenous immunoglobulins (IVIG) have been used to provide temporary benefit in circumstances similar to those in which PE is used. Myasthenia Gravis (MG) Treatment nCrisis: respiratory and bulbar complications require appropriate supportive measures, e.g. assisted ventilation and/or nasogastric feeding. nPE and IVIG are needed. 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) Definition nIn the paraneoplastic disorder, Abs against tumor antigens cross-react with voltage- gated calcium channels involved in acetylcholine release, leading to a disturbance of NMT. Lambert-Eaton Syndrome (LEMS) Etiology nIn 1957, Lambert and Eaton described a myasthenic syndrome that was electrophysiologically distinct from MG. nan archetypal paraneoplastic neurologic disorder, frequently associated with SCLC. noccasionally associated with pernicious anemia. Lambert-Eaton Syndrome (LEMS) Clinical Manifestations nLEMS is more common i