Introduction
Myasthenia gravis(myasthenia gravis, MG) is an autoimmune disease in the conduction of striated muscles and neuromuscular junctions. It is characterized by muscle fatigue, morning rest, rest, or reduction with cholinesterase inhibitors. Often involved with extraocular muscles, masticatory muscles, swallowing muscles and respiratory muscles. In severe cases, the ball is paralyzed. The distribution of affected muscles varies from person to person, not from the paralysis that occurs when a nerve is damaged. This disease should be called acquired autoimmune myasthenia gravis, usually referred to as myasthenia gravis.
Cause
(1) Causes of the disease
1. Myasthenia gravis is an autoimmune disease that affects the transmission of neuromuscular junctions. The exact pathogenesis is still unclear, but there are still many studies on the disease. Among them, the most studied are myasthenia gravis and The relationship between thymus and the role of acetylcholine receptor antibodies in myasthenia gravis, and a large number of studies have found that the number of acetylcholine receptors (AchR) on the postsynaptic membrane at the neuromuscular junction of patients with myasthenia gravis is reduced, and the receptor site exists. Anti-AchR antibodies, and deposition of IgG and C3 complexes on the postsynaptic membrane.
It has also been shown that the increase in anti-AchR antibodies in serum and the reduction in the number of effective AchRs caused by deposition on the postsynaptic membrane are the main causes of this disease. The thymus is the main site of AchR antibody production. Therefore, the occurrence of this disease is generally closely related to the thymus. Therefore, regulating human AchR, increasing its number, dissolving deposition on postsynaptic membrane, and inhibiting the production of anti-AchR antibodies are the key to cure this disease.
2. Genetic susceptibility In recent years, human leukocyte antigen (HLA) studies have shown that the incidence of MG may be related to genetic factors, according to the age of MG, gender, thymoma, AChR-Ab positive, HLA correlation and treatment response MG can be divided into two subtypes: MG patients with HLA-A1, A8, B8, B12 and DW3 are mostly female, 20 to 30 years old, with thymic hyperplasia, AChR-Ab detection rate is low, taking The anti-cholinesterase drug has poor curative effect, and the early thymus removal effect is better; the MG patients with HLA-A2 and A3 are mostly male, 40 to 50 years old, and more thymoma, the detection rate of AChR-Ab is higher, cortex The efficacy of steroid hormones is good; among the 850 MG patients diagnosed and treated by Xu Xianhao in China, there are 2 pairs of twins (both sisters).
3. Recent studies have found that MG is associated with non-MHC antigen genes, such as T cell receptor (TCR), immunoglobulin, cytokines, and apoptosis (apoptosis). TCR gene rearrangement is not only related to MG, but may be related to Related to thymoma, determining the TCR gene rearrangement in MG patients can not only help early diagnosis of thymoma, but also the basis of MG-specific treatment.
4. In MG patients, peripheral blood mononuclear cells (MNC) have decreased adrenal glucocorticoid receptors and normal plasma cortisol levels. Animal experiments suggest that the reduction of adrenal glucocorticoid receptors is easy to induce EAMG.
(two) pathogenesis
Normal fatigue is the continuous reduction of muscle release and the decrease in the number of Ach. The muscle weakness or muscle morbid fatigue of MG is a decrease in AchR at NMJ leading to a transmission disorder. The binding of Ach to AchR produces an endplate potential sufficient for contraction of muscle fibers. NMJ of MG can not effectively expand into the action potential of muscle fibers due to the decrease in the number of AchRs and antibody competition, and the endplate transmission is blocked and the muscle contractility is weakened. This change is first reflected in the eye muscles and brain innervation muscles with the highest frequency of exercise and the least AchR.
The 125I-labeled α-bungarotoxin-conjugated with the acetylcholine receptor extracted from the human skeletal muscle can detect anti-acetylcholine receptor antibodies in the patient's serum, and the antibody blocks the degradation of the postsynaptic membrane receptor, making itself The antigen (nAchR) activity is reduced and the post-synaptic membrane surface area is reduced. Myasthenia gravis occurs due to a transmission of the neuromuscular junction. In the late stage, the muscle fibers are atrophied and the fibrous tissue is replaced.
Fambrough et al. (1973) demonstrated that MG's basic defect is the apparent lack of AchR on the post-synaptic membrane of NMJ, and the detection of AchR-Ab in the serum of EAMG animals, and the discovery of AchR and AchR-Ab and complement in the postsynaptic membrane by immunofluorescence. Immune complex deposition. Muscle biopsy sections of MG patients also found a significant reduction in AchR, which determined the pathogenicity of AchR-Ab and provided strong evidence for MG autoimmunity. Injecting human AchR-Ab into normal animals can cause disease, and this evidence can meet the diagnostic criteria for autoantibody-mediated diseases (Drachman). About 85% of systemic MG and 50% of ocular muscle type MG patients can detect AchR-Ab, and MG mother's newborn can also find AchR-Ab, making this antibody a reliable and reliable indicator for MG diagnosis.
Abnormal autoimmune response of MG has not been elucidated. About 70% of MG patients have abnormal thymus, 10% to 15% of them have thymoma, 50% to 60% have thymic hypertrophy and lymphoid follicular hyperplasia, and the condition is improved after resection of thymus. The thymus is the immune center and plays an important role in the pathogenesis of myasthenia gravis. Whether epithelial cells (including muscle-like cells) or thymus (lymphoid) cells are immunely attacked, breaking immune tolerance, causing humoral immunity (such as nAchR-Ab) and cellular immunity (such as sensitized T cells), cause The autoimmune response to nAchR is therefore morbid. The thymus is a T cell mature site, and AchR subunit mRNA has been detected in the thymus. The thymus-derived T cells and B cells of MG patients have stronger AchR responses than peripheral blood cells.
In addition, normal and proliferating thymus contain myoid cells, which resemble striated muscle and carry AchR. In certain genetically motivated individuals, a virus has the tropism of AchR-thymocyte-like cells, can damage cells and cause changes in the AchR configuration on the cell surface, induce the formation of AchR-Ab, and also pose a potential risk of tumors. It may be the cause of thymoma in about 10% of MG patients. The thymus of MG patients is rich in AchR-sensitized T cells, and the IgG-type AchR-Ab is activated by antigen-specific T helper cells (CD4), which is produced by peripheral lymphoid organs, bone marrow and thymus plasma cells. However, the thymus is not the only source of AchR-Ab. After the thymus is removed, the patient still has AchR-Ab for a long time. It is possible to stimulate peripheral lymphocytes to produce AchR-Ab by antigen-specific helper T cells.
MG patients may have natural killer T-cell (NKT) and other lymphocyte phenotype changes. It is unclear whether the number and function of NKT cells are related to the pathogenesis of MG.
MG patients are often associated with other autoimmune diseases such as systemic lupus erythematosus, rheumatic and rheumatoid arthritis, Sjogren's syndrome, hyperthyroidism, thyroiditis and polymyositis. Some MG patients do not combine autoimmunity. Disease, but can detect autoantibodies, such as anti-thyroid microsomal and globulin antibodies, anti-nuclear antibodies, anti-gastric cell antibodies and anti-islet B cell antibodies.
The frequency of HLA-B8, DR3 and DQB1 genotypes in patients with MG is higher, suggesting that the onset may be related to genetic factors.
The main pathological changes are as follows:
MG skeletal muscle changes are divided into three stages: coagulative necrosis, lymphatic overflow and inflammatory fibrosis. 8% to 20% of patients with MG develop muscle atrophy, common neurogenic and myogenic damage, showing fractures, proliferation, nuclear central shift, vitreous degeneration and connective tissue hyperplasia with different diameters of muscle fibers.
The incidence of muscle damage in adolescents is high, about 42%, and children are only 12%. The most important lesions occurred at the ultrastructural level of motor endplates. Engel et al. (1976) observed the nerve endings and area of the disease by electron microscopy, NMJ presynaptic membrane widening, and the number of vesicles and the amount of ACh contained in the normal range. Post-synaptic membrane prolongation, the primary synaptic gap is widened from normal 200A° to 400-600A°, synaptic folds are reduced, shallow, surface fracture and shrinkage, lack of secondary folds, basement membrane visible in synaptic space The accumulation of substances constitutes the basis of neuromuscular block, called synaptic denervation.
About 60% of patients with MG develop lymphoid oid hyperplasia, which is confined to the medullary germinal center, and the incidence of young patients is high. 10% to 15% of MG patients with thymoma, MG with thymoma histopathological changes can be divided into three types: epithelial cell type, lymphocyte type and mixed cell type (epithelial cells and lymphocytes), rare thymoma has a shuttle Myeloma and Hodgkin's granuloma, each accounting for about 1%. Thymoma is generally benign.
symptom
The disease can be seen at any age. The age of onset of patients in China is more common in childhood. There are more women in the 20-40 age group. Most of the patients are men after middle age, and more common with thymoma. In neonates born to female patients, about 10% of them undergo a placental transfusion to obtain a nicotiniacetylcholine receptor antibody (nAchR-Ab) for temporary weakness. A few have family history. Insidious onset, there are also violent outbreaks.
1. Traditional classification: eye muscle type, medullary muscle type and whole body type.
(1) Ocular myasthenia gravis: The clinical feature is that the affected skeletal muscle is morbidly fatigued. The symptoms are aggravated after being tired in the afternoon or evening, and are relieved in the morning and after the break, showing a regular morning light and heavy fluctuations. Muscle weakness is usually mild and late in the morning, but it can also be changed. The late stage can be in a state of incomplete paralysis; the whole body muscle is not affected by the average, and the extraocular muscles are most often involved. It is an early symptom and can be confined to the eye muscle for a long time. The lighter eyes are weak, the eyelids are drooping, and the asymmetry is distributed, and the frontal muscles are compensatoryly contracted. Eye movement is limited, strabismus and diplopia appear, and the eyeballs are fixed. The intraocular muscles are generally unaffected and the pupillary reflexes are normal.
(2) medullary (or spherical) myasthenia gravis: the facial muscles, the tongue muscles, the masticatory muscles and the throat muscles are also susceptible; the closed eyes are incomplete, the frontal lines and nasolabial folds are flattened, and the sacral muscles are lower than the upper lip when laughing. Lifting muscles are more powerless, lifting lips and teeth like roaring; chewing weakness, difficulty swallowing, tongue movement is not comfortable; soft diaphragm muscle weakness, pronunciation is nasal; after a short conversation, the tone is low or hoarse.
(3) systemic type myasthenia gravis: neck muscles, trunk and limbs muscles can also be criticized, showing difficulty in raising the head, commonly used hands to support the head; chest tightness, shortness of breath, lack of walking, can not be long-term; wash, comb, dress difficult to support; Exist, no sensory disturbance; respiratory muscles, diaphragmatic muscle involvement, coughing weakness, difficulty breathing, severe illness can lead to death due to respiratory muscle paralysis & secondary aspiration pneumonia. Even the myocardial involvement can suddenly die, the smooth muscle and the bladder sphincter are generally not affected; in severe cases, the limb is weak, the upper limb is heavier than the lower limb, and the proximal end is heavier than the distal end. Occasionally muscle atrophy.
The above classifications are not absolutely separated, often mixed, and some types of symptoms are more prominent. The course of the disease is delayed, during which it can be alleviated, relapsed or worsened. Colds, diarrhea, agitation, overwork and menstruation, childbirth or surgery often exacerbate the condition and even threaten life. Quinine, quinidine, procainamide, penicillamine, propranolol, phenytoin, lithium salt, tetracycline and aminoglycoside antibiotics can aggravate symptoms and avoid use. Clinical examination of the affected muscles is prone to fatigue, continuous activity leads to temporary muscle weakness, and short-term rest after improvement is a characteristic manifestation of MG; affected muscle weakness does not conform to any single nerve, nerve root or central nervous system lesion distribution; progressive case involvement muscle Mild muscle atrophy, normal feeling, usually no change in reflexes.
Clinical classification:
1.Osserman classification:
Type I: Eye muscle type (15-20%), simple extraocular muscle involvement. Symptoms are mainly caused by extraocular muscle involvement, which manifests as ptosis on one or both sides of the eye, with diplopia or strabismus. Adrenal cortical hormone therapy is effective and the prognosis is good.
Type II: Systemic type, involving more than one group of medullary muscle groups, the condition is heavier than type I, involving the neck, the back, the back and the trunk muscles of the limbs. According to its severity, it can be divided into IIa and IIb.
Type IIA: mild systemic type (30%), slow progression, no crisis, often accompanied by extraocular muscle involvement, no chewing, swallowing and dysarthria, lower extremity weakness, weakness in the floor, no chest tightness or difficulty breathing symptom. Good response to drugs and good prognosis.
Type IIB: Moderate systemic type (25%), skeletal muscle and medullary muscle are severely affected, obviously weak, can still be self-care, accompanied by mild dysphagia, when the juice is improperly coughed, feeling chest tightness, breathing Not smooth.
No crisis, drug sensitivity is poor.
Type III: severe acute (15%), with severe symptoms, rapid progression, peaking in weeks or months, and high incidence of thymoma. Crisis can occur, the drug effect is poor, tracheotomy or assisted breathing is often required, and the mortality rate is high.
Type IV: late onset severe type (10%), the symptoms are the same as type III, from type I to type IIA, type IIB, after more than 2 years of progress, gradually developed. Poor medication and poor prognosis.
Type V: Muscular atrophy, muscle atrophy occurs in the first half of the year, life can not take care of themselves, difficulty swallowing, food is mistakenly into the trachea and is pulled out of the nostrils. Unclear or accompanied by chest tightness and shortness of breath. Those with secondary muscular atrophy due to long-term muscle weakness are not of this type. The course of the disease is repeated for more than 2 years, often developed from type I or type II.
Crisis refers to a sudden increase in muscle weakness, especially the respiratory muscles (including the diaphragm, intercostal muscles) and the severe weakness of the throat muscles, leading to difficulty breathing, increased secretions of the throat and trachea and unable to be discharged, requiring drainage or artificial respiration. Mostly induced on the basis of severe muscle weakness, accompanied by thymoma is more prone to crisis. Crisis can be divided into three types:
(1) Myasthenia gravis is caused by the increase of muscle weakness in the disease itself. At this time, the cholinesterase inhibitor is often insufficient in dosage, and the muscle strength is improved after increasing the dose or intravenous injection of Tengxilong. Often caused by a cold, it can also occur after the application of neuro-muscular blockers (such as streptomycin), high-dose corticosteroids and thymus radiation therapy or surgery.
(2) Cholinergic crisis is due to cholinesterase inhibitory drug overdose, which prevents Ach from being hydrolyzed, and excessive accumulation of synapses, showing cholinergic toxicity; muscle weakness, fasciculation (nicotine-like reaction) Endplate membrane excessive depolarization); pupil dilation (less than 2mm in diameter under natural light), sweating, increased saliva (muscarinic reaction), headache, nervousness (central nervous response). The symptoms of Tengxilong’s inability to inject did not improve, but worsened.
(3) The ruthenmic crisis temporarily disables the cholinesterase inhibitor, and increasing the dose does not help.
2. Other types:
(1) Neonatal MG: About 12% of MG mothers have difficulty in sucking, crying, limb weakness, and typical symptoms of respiratory insufficiency. Symptoms appear within 48 hours of life and last for several days to several weeks. Symptoms progress progressively until they disappear completely. AchR-Ab can be found in both mothers and children, and the symptoms disappear with decreasing antibody titers. Plasmapheresis can be used to treat children with severe respiratory insufficiency, and ventilator support and nutrition are also key to treatment.
(2) Congenital MG: rare, but the symptoms are serious. Usually in the neonatal period asymptomatic, the main symptoms in infancy are eye muscle paralysis, limb weakness is also obvious, with a family history. AchR-Ab was negative, but repeated electrical stimulation was positive. It is known that ion channel diseases caused by mutations in the AchR gene include slow channel syndrome and fast channel syndrome. The former is an abnormal extension of the ion channel open period, which enhances the Ach response, especially the extensor muscle strength of the forearm is weakened, quinidine is effective, and the extended open period is shortened; the latter has a weakened Ach response. It is known that the 24 mutations in the AChR w subunit are autosomal recessive, causing a severe loss of endplate AchR. Anticholinesterase drugs may be effective.
(3) Drug-induced MG: may occur in patients treated with penicillamine for rheumatoid arthritis, scleroderma, and hepatolenticular degeneration. Clinical symptoms and AchR-Ab titers were similar to adult MG, and symptoms disappeared after discontinuation.
diagnosis
The diagnosis is based on partial or systemic skeletal muscle fatigue, fluctuating muscle weakness, post-activity exacerbation, post-restor reduction and morning light weight, physical examination without other neurological signs, low frequency repeated electrical stimulation amplitude reduction, cholinesterase inhibitor Therapeutic efficacy and pharmacological characteristics such as hypersensitivity to arrow poisons, as well as increased serum AchR-Ab.
Diagnostic signs in the early stages of the disease include drooping eyelids, diplopia, difficulty in speaking, difficulty in swallowing, and mild muscle weakness. Fatigue occurs after continuous activity of the cranial nerves. For example, gazing at the ceiling can increase the drooping of the eyelids, gaze or read 2~ Double vision appears after 3 minutes, and can be recovered after a short break. Cases with difficult diagnosis may be fatigue (Jolly) test, Tengxilong or neostigmine test, AchR-Ab test, nerve repeat electrical stimulation test, and the like.
Identification
1. Lambert-Eaton syndrome (Lambert-Eaton syndrome) Most men over 50 years old, about 2 / 3 with cancer, the most common small cell lung cancer; mainly the weakness of the trunk muscles of the proximal extremities, lower extremity symptoms than the Upper limbs; weight loss and fatigue, slow action. Muscles feel tired after the activity, but if the contraction continues, the muscle strength can be temporarily improved; occasionally the extraocular muscles and the medulla oblongata muscles are involved; about 1/2 cases have abnormal limbs, dry mouth, impotence; Esterase inhibitors are ineffective for treatment. The tendon reflex is weak but there is no muscle atrophy. The myasthenia gravis is more common in women under 40 years old; often accompanied by thymic tumors; the whole body muscles can be affected, the muscles with the most activity are the earliest; the muscles are weak, the morning light is heavy, the activity is aggravated, and the rest is reduced or disappeared after the rest; Not affected; cholinesterase inhibitors are effective. The identification points are shown in Table 1.
2. MG with thyrotoxicosis Some authors believe that MG is associated with thyrotoxicosis. Oxidative ocular paralysis is usually judged by eyeball protrusion (early inconspicuous) and no response to neostigmine.
3. Lupus erythematosus and polymyositis No extraocular muscle paralysis, but MG can coexist with autoimmune diseases.
4. Neurosis patients complained of muscle weakness is actually fatigue, self-reported double vision (short symptoms when tired) and throat tightness (sickness ball), but no sag, strabismus and so on. Conversely, MG can also be misdiagnosed as neurosis or snoring.
5. Progressive extraocular tendon and congenital muscle weakness can also be misdiagnosed as MG. The first two are attached to the extraocular muscles such as the diaphragm and are permanently damaged, and do not respond to neostigmine. Another possibility is that the anti-cholinesterase drug does not respond, erroneously excludes MG, and attention should be paid to electromyography of other muscles.
6. MG patients with no sagging or strabismus, but dysarthria can be misdiagnosed as MS, polymyositis, inclusion body myositis, stroke, motor neuron disease and other neurological diseases, should be noted.
7. Progressive muscular dystrophy The early pharyngeal shoulder strap muscle type and the Guillain-Barré syndrome Fisher variant may have sag, but the Fisher type sputum reflex disappears or ataxia occurs, and EMG examination can be identified.
8. Botulism acts on the presynaptic membrane, leading to NMJ transmission disorders and skeletal muscle spasm. It is improved with the symptoms of Tengxilong or Xinsi, and is easily confused with myasthenia gravis. Early manifestations of blurred vision, diplopia, ptosis, strabismus and eye muscle spasm can be misdiagnosed as MG. Botulism is usually dilated, the photoreaction disappears, and the bulbar muscles, trunk muscles, and limb muscles are rapidly involved.
9. Organophosphorus pesticide poisoning and snake bite can cause cholinergic crisis, but there is a history of clear poisoning and a history of snake bites.
10. Progressive muscular dystrophy Eye muscle type (Kiloh-Nevin type) is more common in young adults, insidious onset, no fluctuations in the disease, mainly invading the extraocular muscles, severe eyeball fixation; family history, serum muscle zymogram and Muscle biopsy and the like can be identified.
complication
Because the muscle weakness patients cannot maintain their basic life and vital signs due to difficulty in breathing or swallowing, they are called muscle weakness. The incidence rate is about 9.8%~26.7% of the total muscle weakness.
According to the causes of myasthenia gravis, it can be divided into three types: myasthenia gravis, cholinergic crisis and ruminant crisis.
1. Myasthenia gravis is caused by disease progression and insufficient anti-cholinesterase drugs. Clinical manifestations of swallowing, coughing, respiratory distress, difficulty, and even stop. Physical examination showed dilated pupils, sweating, bloating, normal bowel sounds and improved symptoms after neostigmine injection.
2. Cholinergic crisis accounts for 1.0% to 6.0% of the number of crisis cases, due to an excess of anticholinesterase. In addition to the common features of muscle weakness, the patient's pupils are narrowed, sweating, muscles are beating, bowel sounds are hyperthyroidism, and the symptoms of the muscles are increased.
3. The rumination crisis is caused by infection, poisoning and electrolyte imbalance. After the application of anti-cholinesterase drugs, it can be temporarily relieved, and then the critical state is aggravated.
Myasthenia gravis may be associated with other diseases, such as thymoma, followed by hyperthyroidism, a small number may be associated with rheumatoid arthritis, lupus erythematosus and autologous hemolytic anemia.
treatment
Western medicine treatment
Treatment plan
(1) The preferred option: thymus removal, if the condition is significantly worse after surgery, can be supplemented by plasma exchange, high-dose immunoglobulin, adrenal corticosteroids and cholinesterase inhibitors.
(2) Secondary selection program: patients with severe disease can not be removed by thymectomy can be treated with plasma exchange or high-dose immunoglobulin, with adrenal corticosteroids, gradually transition to corticosteroids alone, the condition is improved and stable after 2 months of thymus removal, surgery After the original dose was maintained for 2 months, and then slowly reduced for 2 to 4 years, until the suspension.
(3) Three-choice program: MG patients who cannot or refuse thymus removal, plasma exchange or high-dose immunoglobulin is preferred for critically ill patients, corticosteroid therapy is preferred for non-critical patients, and azathione may be added during corticosteroid reduction. Other immunosuppressive drugs such as sputum reduce or reduce rebound.
(4) Four-choice protocol: MG patients who refuse or can not be removed by thymus and refuse or can not tolerate corticosteroid treatment can be treated with immunosuppressive drugs such as cyclophosphamide.
2. Main treatment methods
(1) Cholinesterase inhibitors: commonly used as neostigmine, bromide, and ampochloramine (enzyme inhibitor). Bromide is most commonly used, with fewer side effects. The initial amount of adult is 60 mg orally, every 4 hours. The dosage can be increased according to the clinical manifestation. If the patient has difficulty eating, the medicine can be taken 30 minutes before the meal. If the patient has difficulty walking in the morning, he can take long-acting bromide 180mg before getting up. Its muscarinic side effects are abdominal pain, diarrhea, nausea, vomiting, salivation, increased bronchial secretions, tearing, dilated pupils and sweating. Pre-administration of 0.4 mg of atropine can alleviate the symptoms of muscarinic, but excessive atropine can cause Mental symptoms. There is no evidence that the combination of the two drugs is better than the single drug treatment. Although anticholinergic drugs have better curative effects, there are limitations, such as eyelid MG drooping, which can improve eyelid ptosis, but some patients often have double vision; systemic MG can significantly improve symptoms, but it is difficult to eliminate. Such drugs can inhibit the activity of cholinesterase, protect Ach from hydrolysis, improve the transmission of neuromuscular transmitters, and temporarily improve muscle strength, which is an effective symptomatic therapy. Usually, pyridostigmine is used in 60-120 mg, 3 to 4 times/d, and is administered half an hour before a meal. Starting from a small dose, gradually increase the amount, adjust to the muscle strength to improve, can maintain eating and living activities, avoid overdose. In order to relieve side effects such as abdominal pain and runny, a small amount of atropine can be taken at the same time. In addition, long-term abuse of cholinesterase inhibitors should be prevented so as not to impede the repair of nAchR.
(2) Immunosuppressive drugs:
1 corticosteroids: strong inhibition of T cells. Inhibition of thymic germinal center formation reduces the synthesis of nAchR-Ab. Applicable to all types of MG, eye muscle type children are quick and obvious, but relapse every time they catch a cold. Can also be used before and after thymoma surgery. Adrenal corticosteroids are usually effective and safe for moderate to severe MG patients of all ages, especially middle-aged people over 40 years of age, whether or not they have undergone thymectomy, often with anticholinesterase. Often used for preoperative management of thymectomy, or because of the late onset of surgery, the transition period after thymectomy can also be used. Patients with this therapy should take high protein, low sugar, and supplement the potassium-rich diet, if necessary, take antacids. There are currently three treatment methods used;
1 High-dose declining every other day: every other dayPrednisoneAt the beginning of 60~80mg/d, the improvement of symptoms usually occurs within 1 month. After a few months, the effect reaches a peak. At this time, the dose can be gradually reduced until the maintenance dose of 20~40mg/d is taken every other day. The selection criteria for the maintenance amount is the minimum dose that does not cause the symptoms to deteriorate.
2 low-dose incremental day-to-day therapy: start with prednisone 20mg/d every other day, increase 10mg per week until 70~80mg/d every other day or achieve obvious curative effect; the improvement rate of the disease is slowed down, the maximum curative effect is common after medication 5 months; the chances of worsening the condition are less, but the date of worsening the condition may be delayed, which makes the vigilance of doctors and patients weakened, so it is more admired for large doses of next-day therapy.
3 high-dose shock therapy: high-dose every other day therapy can not alleviate or recurring crisis cases, can be triedMethylprednisolone1000mg/d, combined with 3d shock therapy. Experience has shown that a course of treatment often fails to achieve satisfactory results, and one course can be repeated every two weeks, and two to three courses can be performed. The dosage, interval and number of treatments should be individualized according to the patient's specific conditions. Side effects of corticosteroids such as Cushing's syndrome, hypertension, diabetes, gastric ulcer, cataract, osteoporosis and withdrawal syndrome cannot be ignored.
2 cytotoxic drugs: patients who are ineffective in the treatment of corticosteroids or have thymoma, can be treated with cytotoxic drugs. Cyclophosphamide (CTX) inhibited B cells significantly. The usual amount for adults is 100 mg/d. For repeated crises, intravenous infusion of 200 ~ 400mg / d, the total amount of about 10g is effective. Patients with poor efficacy after thymectomy can be combined with chemotherapy:Cyclophosphamide800mg/m2, doxorubicin 50mg/m2Vincristine1.4mg/m2, plus prednisone 40mg/m2, every 3 to 4 weeks for a cycle, and some have significant effects. Pay attention to toxic side effects and blood.Azathioprine(AZA) inhibits CD4 T cells and is generally effective after 8 weeks.
(3) Plasma exchange: plasma exchange or preoperative treatment of patients often used for thymectomy to avoid or improve postoperative respiratory crisis. Generally, 5% of the blood is replaced before surgery to ensure that the patient can withstand surgery; also for other types of crisis, the vast majority of patients have varying degrees of symptoms, which can last for several days or months. The law is safe but expensive.
(4)Immunoglobulin: 0.4g / (kg · d) intravenous drip, used in 5d therapy for various types of crisis. Side effects include headache, aseptic meningitis, and flu-like symptoms. Symptoms can be relieved within 1~2 days. This method is simpler than plasmapheresis, and both therapies are used when the condition worsens.
(5) Immunosuppressive agents: There is no improvement in hormone therapy within six months, and azathioprine or cyclophosphamide should be considered. The initial dose of adult azathioprine is 1~2mg/(kg·d), and the maintenance dose is 3mg/(kg·d), which is taken together with food to prevent nausea. Should pay attention to the susceptibility of bone marrow suppression and infection, blood should be checked regularly, if the white blood cells are less than 3 × 109 / L, it should be stopped, should also pay attention to liver and kidney function.
(6) Thymus radiation therapy or thymectomy: For thymus radiotherapy or surgical resection, it can directly inhibit or eliminate the source of autoimmune response in the thymus and tumor lesions. To date, thymic radiotherapy is still a truly effective treatment for MG, and it is called "non-surgical surgical treatment." Applicable to patients with poor drug efficacy, recurrence, large or multiple thymoma inoperable, or malignant tumors can be added after surgery. The commonly used dose is 40 ~ 50Gy, using 60 cobalt (60Co), linear accelerator and electron beam irradiation, the effect is relatively stable.
Thymectomy: Thymectomy is still the basic treatment of MG, suitable for systemic MG, poor efficacy or multiple crisis patients. Middle-aged female patients with 3 to 5 years of onset have a very good effect. In all types of MG patients with thymoma, although the curative effect of surgical resection is poor, it is still necessary to seek surgical resection of the lesion. Blalock et al. performed a thymectomy on 20 patients with myasthenia gravis and found that thymectomy in patients with myasthenia gravis is an important treatment for myasthenia gravis. Surgical treatment has obvious advantages in symptom control compared with non-surgical treatment. Most authors believe that medical treatment is ineffective, or that there are adverse side effects with medication, and when limited, thymectomy is performed. There are also authors (Jaretzki et al. 1988, Cop-per et al. 1988) who advocate surgery at an early stage, and the shorter the course of the disease, the better the surgical outcome. Due to the high surgical risk of patients with severe cases and poor resistance, it is necessary to treat the surgical period to reduce the recent mortality rate.
1 preoperative preparation and precautions: In addition to routine preoperative smoking, correction of hypoproteinemia, anemia, the use of anti-cholinesterase drugs to control symptoms. Corticosteroids were administered 1 month before surgery, and human gamma globulin (gamma globulin) was injected in combination with plasma exchange or filtration. All patients should be evaluated by X-ray and CT scan before surgery to exclude the presence of thymoma. Try to avoid using drugs that may interfere with the conduction function between the nerves and muscles and aggravate the symptoms of muscle weakness.QuinidineQuinine,Propranolol(Heartan), polymyxin, tetracycline antibiotics, aminoglycoside antibiotics; anesthetic ether, muscle relaxant including myostatin (follham); avoid the use of central nervous system inhibitors such as morphine. AchRab, PsMab and CAEab were routinely examined before surgery.
2 anesthesia: general anesthesia is preferred, because the surgery may damage the pleura and enter the chest. Anesthesia was induced by short-acting barbiturates, followed by general anesthesia, and electrocardiogram, blood pressure and blood gas analysis were continuously monitored during the operation. Avoid using anticholinesterase drugs during surgery.
3 Incision: The anterior sternal incision or the incision through the neck can be used to enlarge the thymectomy. Transcervical incision combined with video-assisted thoracoscopic resection of the thymus is easy to operate, with minimal trauma and low postoperative rate, which is easy for patients to accept. Most surgeons use a midline incision in the sternum, or a partial incision in the sternum, or a transverse incision in the fourth intercostal space of the sternum. Many reports suggest that the efficacy of thymectomy for myasthenia gravis is associated with a complete removal of thymus tissue. Because ectopic and vagus thymus can be widely distributed in mediastinal fat, it is believed that cleaning the neck and mediastinal fat to clear ectopic thymus tissue can improve long-term efficacy.
4 surgical methods:
A. Transthoracic thymectomy: Take the supine or lower semi-recumbent position, through the sternum, from the sternum to the fourth rib level, saw the sternum, and if necessary, do a full sternotomy. For large thymoma, secondary surgery, or obese short-necked patients, a transverse transverse incision can be used. After the bone wax was applied to both sides of the sternal incision, the anterior superior mediastinum and the cervical root were exposed with a sternum retractor.
Since the tumor is located in the upper part of the incision, pushing the left and right pleura, the exposed grayish red thymus is significantly different from the surrounding mediastinal yellow fat. The thymus gland is sharply dissected upward from the side of the thymus. The mediastinal extension of the deep fascia of the neck is confirmed below the sternal thyroid muscle. The left, right and middle thymus arteries are ligated and cut after separation. Avoid the phrenic nerve to the lateral side, otherwise it will cause postoperative palsy. Separate and cut 1 to 2 branches into the thymus vein below the left unnamed vein. The thymus on one side or both sides can enter the posterior part of the innominate vein. On both sides of the upper pole, there are often branches of arteries from the inferior thyroid artery. Be careful not to damage and avoid accidental injury to the parathyroid glands. Careful examination of the mediastinum with or without ectopic thymus or residual thymus, studies have shown that there may be tiny thymoma or hyperplastic thymus tissue in the adipose tissue from the neck to the diaphragm, which should be removed during surgery.
Thorough hemostasis, especially attention to bleeding in the anterior and posterior sternal and sternal sections. The drainage tube was placed at the lowest position of the anterior mediastinum, and the appropriate enlarged pleural notch that could not be repaired by partial pleural resection was changed to chest drainage. The stainless steel wire is fixed to the open sternum, and the inner mammary artery on both sides of the sternum is not damaged. The bleeding of the wire through the sternum can be electrocoagulated to stop bleeding. Note that the surrounding wire stump is placed in a position to avoid discomfort after surgery, and the periosteum, pectoralis major fascia and skin are layered.
B. Transcervical thymectomy: Now the multiple thymus is removed by video-assisted thoracoscopic surgery. Take the supine position, raise the shoulders, and lean back. Take the 2cm of the sternal fossa as the midpoint and bend the arc incision along the skin, and the sternocleidomastoid muscles on both sides. The flap is freed under the plane of the platysma, up to the thyroid level, and the level of the sternum is lowered. The strip muscles are separated in the middle, and the thymus can be seen under the sternum thyroid muscle. After ligating and cutting the inferior thyroid vein, the left upper pole of the thymus can be seen. Leave the ligature for traction. Analyze the right upper pole by the same method, and ligation before cutting, the two poles are fully released to the sternal notch level, and the anterior blood vessel is the unknown vein. When the thymus is released from the posterior wall of the sternum and the upper poles are pulled upward, the thymus vein can be seen and the ligation is cut. Free the right side of the thymus and extend down to the right lower pole. The thymus is freed from the aorta and the front of the pericardium, and finally the left lower pole and its tail end are freed, which often extends down to the aortic window. After all the thymus was freed, the thymus was removed together with the anterior mediastinal fat. After the drainage was placed in the mediastinum, the incision was sutured layer by layer. After suturing the platysma, the drainage tube is removed and the lungs are fully expanded. Therefore, although there is a small rupture on one or both sides of the pleura, it is not necessary to drain the chest tube.
5 postoperative treatment: postoperative patients are not awake to indwell the tracheal intubation back to the ward and respiratory monitoring, clear respiratory secretions, such as 3 to 5 days can not remove the auxiliary breathing, should do tracheotomy, gastric tube feeding and drug treatment The patient's awake throat muscles return to normal: they can breathe spontaneously, cough, and blood gas analysis indicators indicate that the tracheal intubation can be removed when the respiratory function is normal, encouraging patients to cough, cough, and strengthen nursing.
Patients with myasthenia gravis due to surgical trauma, changes in immune function and postoperative sensitivity changes may cause aggravation of muscle weakness or sputum toxic reaction, and continue anticholinergic drug therapy. The dose is adjusted according to the condition. Patients who had prednisone preoperatively received only hormonal drugs, orally or intravenously. Stop the drug until the last symptom disappears. If thymoma is found during surgery, the surrounding tissue is found to be infiltrated during surgery, and patients with unstable symptoms after surgery should be treated with normal mediastinal area before radiotherapy.
6 Surgical effect: early postoperative effect is good, the mortality rate is 0% to 2%, the influence of the patient's age, gender, disease classification and other factors on the surgical outcome, clinical data reports: generally considered myasthenia gravis with thymoma, The surgical effect is not as good as that of no tumor; young women with thymic hypertrophy or hyperplasia type II myasthenia gravis have better surgical results; preoperative acetylcholine receptor antibody titer is higher and postoperative decline to normal level good. Because the range of myasthenia gravis is difficult to stage, drug therapy, plasma exchange, thymus radiotherapy, and thymectomy cannot be compared and evaluated.
(7) Other treatments: In addition to the above common treatments, there are percutaneous puncture thymus microwave intervention, plasma exchange or purification, gamma globulin high-dose intravenous immunoadsorption and anti-CD4 - McAb treatment. According to the dialectical diagnosis of MG, MG believes that it belongs to spleen and kidney deficiency. It is often treated with Buzhong Yiqi Decoction as the basic treatment and reuse of jaundice.
(8) Treatment of crisis: emergency rescue is required. First, keep the airway open and maintain effective breathing. Respiratory muscle paralysis is light, encouraging cough, oxygen, or prone, low head, chest compression artificial respiration. If the breathing and cough are severely weak and phlegm, the trachea should be intubated or the trachea should be opened early for artificial respiration and sucking. Check the dose and time of administration of the original cholinesterase inhibitor, pay attention to insufficient or excessive dose. For different types of crisis, the corresponding drug treatment: for the muscle weakness crisis, first intramuscular injection of neostigmine 1mg, and then according to the condition, 0.5 to 1mg every 0.5 to 1 hour. A small number of medications can avoid a cholinergic crisis. If the muscle weakness is aggravated, it indicates that a cholinergic crisis has occurred, and the cholinesterase inhibitor is stopped immediately. It can be intravenously administered with 1 to 2 mg of atropine. For rumination crisis, it is advisable to stop the above medication, intravenous inputDexamethasoneOr methylprednisolone sodium succinate 500mg, once / d, for 6 days, can restore the function of muscle motor endplates, and later restore the cholinesterase inhibition drug dosage. Most of the dangers are caused by infection, and anti-infective drugs such as penicillin can be given. Myasthenia gravis can be associated with heart damage, and attention should be paid to stabilizing blood pressure.
Pan Tiecheng and other basic ideas for the treatment of myasthenia gravis are as follows:
1 eye muscle type. Especially for children, it is advisable to use prednisone "medium dose shock, small dose maintenance" therapy.
2 bulbar muscle type. AChEI and corticosteroid therapy should be preferred.
3 eye muscle type and bulbar muscle type patients. After treatment with corticosteroids or pyridostigmine, the symptoms are repeated, and when the effect is gradually reduced, other immunosuppressive agents such as cyclophosphamide, azathioprine or cyclosporine should be used.
4 eye muscle or systemic patients. The above-mentioned treatment is not effective, and if it is conditional, a large dose of human gamma globulin (gamma globulin) intravenous infusion therapy can be used.
5 For the crisis (especially the myasthenia crisis with cholinergic crisis), thymus preoperative preparation, obvious symptoms after thymectomy, or systemic drug treatment is not good, plasma exchange therapy can be used.
6 systemic drug treatment is not effective or thymoma can not be treated with thymus radiotherapy.
7 patients with thymoma, other types of thymic disease or systemic MG patients gradually reduced drug treatment. Thymectomy can be used (all must be treated in perioperative period according to the specifications).
8 thymoma can not withstand surgery or surgery, you can choose thymus X knife treatment.
9 All MG patients, including thymus surgery, in order to improve efficacy, reduce hormone dosage, prevent recurrence and consolidate treatment effects, can be supplemented with traditional Chinese medicine (such as: Fuzhengqiangjin tablets) adjuvant treatment.
The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary.
prevention
To enhance physical fitness, pay attention to the following aspects:
1. Encourage your spirits and keep your emotions comfortable
Spiritual emotional activities are closely related to the physiological changes of the human body. The spirit is comfortable and the spirit is pleasant. The air is smooth, the blood and blood are harmonious, the function of the organs is coordinated, the vitality is strong, and it is not easy to occur. Even if it happens, it can recover quickly; on the contrary, If the emotions are not smooth and the spirit is depressed, the air machine can be reversed, the yin and yang are dysfunctional, the viscera function is abnormal, and the righteousness is weakened, which occurs. Clinically, the occurrence of this disease is often related to long-term mental stress or excessive thinking, sadness and other emotional changes. If the patient's emotional fluctuations often cause the disease to develop or worsen during the recovery, the patient is in the process of treatment and recovery. We must pay attention to mental health, keep the mind calm and clean, do not greedy and think, make the infuriating and smooth, and keep the spirit in mind. Only in this way can the disease recover soon.
2. Reasonable, don't be partial
Reasonable and sufficient is the necessary condition to ensure the growth and development of the human body. "Five flavors of the entrance, hidden in the stomach, to raise the five Tibetan gas." Insufficient lack of, affecting qi and blood biochemistry, leading to physical weakness, on the contrary, excessive can damage the spleen and stomach, resulting in a decline in physical fitness over time, therefore, patients with muscle weakness in the top of the sputum mix, coarse grain and fine grain, children must correct bad Habits, in order to make the patient's physical condition stronger, and the righteousness is strong, so that the disease can recover as soon as possible.
3. Work and rest, living is always
The onset of muscle weakness has a lot to do with overwork. The patients are often overworked, overexposed, labored day and night, or dysfunctional because of running around, consuming blood and physique, and the body is declining. And development, so patients in this disease in the recovery process, must have a regular life, work and rest, the only way to cooperate with drug treatment, gradually increase the physical fitness, and restore soon.
4. For patients with clear diagnosis, any drugs that can affect neuromuscular conduction function should be avoided, such as: aminoglycoside antibiotics - streptomycin, kanamycin and gentamicin, etc. , tetracyclines - chlortetracycline, oxytetracycline, and the reduction of sarcolemma excitatory drugs - quinine, quinidine, procaine and so on. Also disable the propranolol,PhenytoinandPenicillamineWait.
简体中文