_gravis重症肌无力_1课件

Myasthenia Gravis 重症肌无力 Department of Neurology Xuanwu Hospital Muscular Disorders q Disorders of the neuromuscular junction q Disorders of muscle fibers Disorders of the Neuromuscular Junction Presynaptic membrane Lambert-Eaton syndrome Botulism Synaptic cleft Organophosphate intoxication Postsynaptic membrane Myasthenia gravis Disorders of Muscle Fibers (Myopathies) Muscular dystrophies Congenital myopathies Membrane myopathies (chanelopathies) Inflammatory myopathies Metabolic myopathies I. Definition of Myasthenia Gravis MG is a disorder of the neuromuscular transmission owing to antibody-mediated attack on acetylcholine receptors(AchR) at neuromuscular junctions. Muscle weakness occurs in association with continuous effort, and improves with rest . . Etiology and Pathogenesis An autoimmune mechanism, operative at the neuromuscular junction Weakness and fatigue are due to the failure of effective neuromuscular transmission. Neuromuscular junctions 1.Reduced Number of Receptors and the Competitive Activity of Anti-AchR Antibodies 85% of patients with generalized MG 60% of those with ocular MG are positive for anti-AChR antibody. Muscle AChR (Adult) Ach Binds AChR How the antibodies act at the receptor surface of the end plate and impair the neuromuscular transmission? (1) Block the binding of Ach to the Ach receptors (2) Increase the degradation rate of AchRs. (3) Complement mediated destruction of postsynaptic folds 2.The role of thymus in pathogenesis of MG The thymus is an organ that produces cells involved in immune responses. Approximately 15% of MG patients have a tumor of the thymus (thymoma) And 60% have abnormal enlargement (hyperplasia) of the thymus. vBoth T and B cells from the myasthenic thymus are particularly responsive to the AchR, more so than analogous cells from peripheral blood. vMoreover, the thymus contains “myoid cells”(resembling striated muscle) that express surface AchRs. vMaybe a virus with tropism for thymic cells that have AchRs might injure such cells and induce antibody formation. . PATHOLOGY OF MG 1. THYMUS 15% of MG patients have thymoma 60% have hyperplasia of the thymus 2. Pathology of skeletal muscles: In about 50% of patients, muscles contain lymphorrhages, which are focal clusters of lymphocytes near small necrotic foci without perivascular predilection. （淋巴细胞的聚集） The major abnormalities of the neuromuscular junction in MG include (a) reduced length of the postsynaptic membrane, (b) shortening of the synaptic folds and (c) widening of the synaptic clefts . . CLINICAL FEATURES OF MG A. Prevalence: 5/100,000 B. Age: Average age of onset is 20, with a preference for young females below the age of 40, but the disease are more common in males over age 40, especially with thymoma C. Symptoms: the fluctuating nature of myasthenic weakness: The weakness varies in the course of a single day, sometimes within minutes, and it varies from day to day or over longer periods. The weakness worsens towards the end of the day. The factors known to increase weakness include exertion, hot temperatures, infections, emotional upsets, certain drugs (for example, aminoglycosides, phenytoin, local anaesthetics), surgery, menses, and pregnancy. 2. the distribution of weakness: （1）Ocular muscles(levator palpebrae and extraocular muscles) are affected first in about 40% of patients and are ultimately involved in about 85%- -ptosis and diplopia （2）Facial or oropharyngeal muscles are affected- dysarthria, dysphagia, and limitation of facial movements (3) Limb and neck weakness is also common, but in conjunction with cranial weakness. Almost never are the limbs affected alone. 3.weakness is improved by anticholinesterase drugs: D. Signs: Muscle weakness. Muscles wasting is rare. Deep tendon reflexes are intact or may be brisk. There are no objective sensory deficits. Myasthenic Crisis Myasthenic crisis is an exacerbation of myasthenia leading to paralysis of respiratory muscles that requires an urgent respiratory support. This is usually caused by infections, initial high dose steroid therapy, or an inadequate treatment. Patients should be managed in an intensive care unit. In addition to respiratory support, Plasmapheresis or intravenous immunoglobulin treatment may be required for prompt control of the disease. F. Ossermans Original Classification of MG Based on the severity of the disease 1. Ocular myasthenia, where disease is confined to ocular muscles. 2. Generalized myasthenia gravis of mild (a) or moderate (b) intensity. 3. Severe generalized. 4. Myasthenic crisis with respiratory failure. G. Other Types of MG 1. Neonatal MG: 2. Congenital MG 3. Drug Induced MG: Penicillamine. 4. Neuromuscular Junction Blockade (NMJ): Gentamicin and other aminoglycoside antibiotics . DIAGNOSIS OF MG A. History and physical examination: 1. Document weakness occurring with continuous effort and recovering with rest. 2. Common features: 3. Important negative findings: Normal sensory examination, normal bowel and bladder function. 4. Autoimmune diseases associated with MG: a. Thyroid disease (both thyroiditis and autoimmune hyperthyroidism) b. SLE (Systemic Lupus Erythematosus) c. Rheumatoid arthritis d. Other connective tissue diseases e. Pernicious anemia B. Special laboratory tests: 1.Tensilon test: Edrophonium hydrochloride （腾喜龙）, a short-acting anticholinesterase given intravenously (10/sec stimulation of motor nerve to an involved muscle Repetitive Nerve Stimulation 3. Single fiber electromyography The mean interpotential difference between two fibres is called “jitter” and is normally less than 55 sec. In MG, this interval or jitter is increased and is usually 100 sec. Single Fiber Electromyography Normal SFEMG Increased jitter: MG patient 4. Acetylcholine receptor antibody titer: Elevated in 80% of patients with generalized MG and in 50% of patients with ocular MG. 5. Anti-MuSK（肌肉特异性蛋白激酶） antibodies: 6.Anti-skeletal muscle antibody titer: 7. Radiographs of chest: CT of thymus C. Differential diagnosis: 1. Lambert-Eaton Myasthenic Syndrome (LEMS) Weakness and fatigue of proximal muscles There is relative sparing of ocular and bulbar muscles. Strength improves during the first few seconds of voluntary muscle contraction. There is a common association with carcinoma, specifically oat cell carcinoma of the lung.-a paraneoplastic disease. (1)Repetitive nerve stimulation: Low amplitude of the evoked muscle action potential at low rates of stimulation. Marked several-fold increase in amplitude stimulating at rates above 10 Hz. (2) Electron microscopy studies-Decreased numbers of presynaptic active zones and active zone particles. (3)An autoimmune paraneoplastic disease-Responds to steroid, immunosuppressants and plasmapheresis. (4) 突触前膜Ca离子通道蛋白异常 2. Botulism History of ingestion of the contaminated food Generalized weakness, internal and external ophthalmoplegia, and respiratory paralysis. Pupillary dilation The incremental response on repetitive nerve stimulations 3. Drugs induced myasthenia: Penicillamine（青霉胺）, curare（箭毒）, aminoglycosides（氨基糖甙类）, procainamide （普鲁卡因酰胺）, and quinine（奎宁） 4. Ocular myasthenia should be differentiated from progressive external ophthalmoplegia (a mitochondrial disorder), ocular Graves disease, and intracranial space occupying lesions. V. Therapy For MG: A. Anticholinesterase drugs: inhibit acetylcholinesterase and increase availability of the acetylcholine to act on the AChRs. 1. Pyridostigmine bromide 2. Pyridostigmine hydrochloride (Mestinon) 3. neostigmine B. Plasmapheresis C. remove Ach-R antibodies of serum D. yield transient improvement in patients with severe involvement. C. Thymectomy 1. Remove thymoma. 2. Removed early in generalized MG may increases frequency of remissions; best results in young females with hyperplastic gland and high antibody titers. D . Corticosteroid: 抑制AchR-Ab生成，增加突出前膜释放量和促使终板再生、 修复。使用方法有多种，但开始使用一定在医院内，并且有监 护和抢救措施。 initial high dose steroid therapy may worsen the myasthenia, even cause myasthenic crisis the long term use steroids is associ