Disturbance of neuromuscular transmission. Approach to the treatment of neurological diseases, history taking

) manifests itself as symmetrical weakness of the proximal parts, not accompanied by loss of sensitivity. Therefore, the patient should be asked the following questions.

1. Proximal leg weakness: Can the patient get out of a car, get off the toilet in the restroom, or stand up from a chair without using their hands?
2. Proximal arm weakness: Can the patient lift and carry small children, grocery bags, trash bags, briefcases, etc.?
3. Symmetrical weakness: Does the weakness involve both arms or legs? (Although myopathies, typically a generalized process, often present somewhat asymmetrically, weakness limited to one limb or one side of the body is rarely associated with a myopathy.)
4. Sensation: Is there numbness or loss of sensation? (Although pain and cramps occur in some myopathies, any disease limited to muscles should not have sensory disturbances.)
5. If the history suggests a muscle disease, what signs might be found on a neurological examination?

Examination should reveal symmetrical weakness of the proximal limbs, not accompanied by loss of sensation. The muscles are usually without atrophy and fasciculations, and the muscle mass is normal or slightly reduced. Tendon reflexes remain within normal limits or are slightly reduced.

7. What symptoms of neuromuscular transmission disorders can be identified when taking anamnesis?

Pathological Fatigue, -i; and. Rapid onset of fatigue from smb. activity that has not caused it before, often associated with illness, pregnancy; may be accompanied by headache, sweating, palpitations, feeling of weakness, decreased performance, and irritability. Prevention: rational change of work and rest, adequate sleep and nutrition with foods containing a large number of vitamins, reduction of stress.

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8. If the history indicates a disorder of neuromuscular transmission, what signs can be found during a neurological examination?

The examination should reveal symmetrical weakness of the proximal parts, increasing with load and accompanied by a decrease in sensitivity. With repeated testing of the mouse's function, their strength decreases and after a short period of rest is restored. Prolonged muscle activity can also cause fatigue, for example, ptosis can increase when looking up for a long time. Weakness is limited only to the most and proximal parts, involving the extraocular muscles, mastication and facial muscles. Trophics, -i; and. 1. Biol. The set of metabolic processes underlying the nutrition of cells, tissues and organs, ensuring the preservation of their structure and function. From Greek trophe - food.

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9. What symptoms of peripheral nerve damage can be identified when taking anamnesis?

In contrast to myopathies and disorders of neuromuscular transmission, when peripheral nerves are affected (peripheral neuropathies), weakness most often predominantly involves distal nerves. rather than the proximal parts. It is often asymmetrical and accompanied by muscle atrophy and fasciculation. Almost always, when nerves are damaged, changes in sensitivity are detected. The following symptoms can be identified from the anamnestic history.

1. Weakness in the distal parts of the feet, does the patient drag or drag his feet when walking, DOES he wear out the socks of his shoes?
2. Weakness in the distal parts of the hands: does the patient often drop objects, can he shake hands firmly?
3. weaknesses: are symptoms limited to any one area (Some, especially in metabolic disorders such as Diabetes mellitus. An endocrine-metabolic disease of a person caused by a lack of insulin in the body or a decrease in its action, the cut is characterized by an increase in sugar levels on an empty stomach, during the day and profound metabolic disorders. Synonym: sugar disease (obsolete), diabetes mellitus. Types: insulin-dependent diabetes (type I) and non-insulin-dependent diabetes (type II). Risk groups: obesity; burdened heredity; indications of a history of impaired glucose tolerance; women with increased blood sugar levels during pregnancy or who gave birth to large children weighing more than 4-4.5 kg; people whose blood contains antibodies to pancreatic beta cells.
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4. Denervation changes: are there decreases in muscle volume (atrophy) or muscle twitching (fasciculations)?
5. Sensory disturbances: Does the patient experience numbness, tingling or paresthesia?

10. If the history indicates damage to the peripheral nerves, what signs can be found during a neurological examination?

Examination may reveal distal weakness, often asymmetrical and accompanied by muscle atrophy and fasciculations, as well as sensory disturbances. Muscle tone may be normal, but is often reduced. Tendon reflexes are usually reduced or not evoked. When autonomic fibers are involved, which often occurs in peripheral neuropathies, trophic changes develop, including thinned, smooth, shiny skin, vasomotor disturbances (for example, swelling and changes in skin temperature), and loss of nails and hair.

11. What symptoms of damage to the spinal roots (radiculopathy) can be identified when collecting anamnesis?

Pain is characteristic of such root lesions. Otherwise, the clinical manifestations of radiculopagnea: asymmetrical weakness with grafting densration (atrophy and phagogenesis of muscles), pain (sensitivity singing - reminiscent of lesions of peripheral seals. Weakness, invariably asymmetrical. Involvement of the lower extremities is most often associated with damage to the L5 and Si nuclei, which permeate the distal parts , while involvement of the upper extremities is most often associated with damage to the C5 and C6 roots innervating the proximal parts. Thus, the anamnestic history of lesions of the roots reveals symptoms similar to manifestations of damage to peripheral nerves, with an additional component in the form of pain, patients usually describe pain as acute, piercing, burning, similar to

1. The first step in treating a patient with a neurological disease should be to determine the location of the lesion.
2. Myopathies cause proximal symmetric muscle weakness without sensory loss
3. Disruption of neuromuscular transmission causes pathological fatigue
4. Damage to peripheral nerves causes asymmetric, predominantly distal paresis with atrophy, fasciculations, loss of sensation and pain
5. Radiculopathies cause radiating pain

AP propagates through activation of Na + channels to nerve endings, where it depolarizes the cell membrane, which leads to the opening of voltage-gated Ca 2+ channels. Ca 2+ ions entering the nerve endings trigger the release of vesicles containing ACh from the presynaptic membrane, as a result of which the latter is released into the synaptic cleft. ACh then binds to receptors on the subsynaptic membrane and opens nonspecific cation channels. Depolarization of the subsynaptic membrane spreads to the postsynaptic membrane, where, after the opening of voltage-gated Na + channels, an AP occurs, which quickly spreads throughout the muscle membrane. ACh is destroyed by acetylcholinesterase, the resulting choline is recaptured by the nerve ending and reused for the synthesis of ACh.

Pathological changes can affect any element of this process. Local anesthetics, for example, inhibit voltage-gated Na + channels of neurons, thereby disrupting nerve transmission to the end plate of the neuromuscular junction. Ca 2+ channels can be blocked by antibodies. Botulinum toxin inactivates the synaptobrevin protein, which is responsible for the binding of vesicles containing ACh to the plasma membrane, i.e., for the release of ACh. Acetylcholine receptors, as well as Ca 2+ channels, can be blocked by antibodies, which, in addition, accelerate internalization and destruction of these receptors. Receptors can also be blocked by curare, which, without having its own effect, competitively inhibits the binding of ACh to receptors.

Succinylcholine (suxamethonium chloride) leads to prolonged stimulation of receptors, prolonged depolarization of the postsynaptic membrane, thereby causing inactivation of postsynaptic Na + channels. Thanks to this action, it is capable, like curare, of blocking neuromuscular transmission of impulses. At low concentrations, acetylcholinesterase inhibitors (eg, physostigmine) facilitate uneven muscle transmission by increasing the availability of ACh at the synaptic cleft. However, in high doses they slow down neuromuscular transmission, because high concentrations of ACh and succinylcholine cause prolonged depolarization of the subsynaptic membrane, thereby inactivating postsynaptic Na + channels. Reuptake of choline by nerve endings may inhibit Mg 2+ ions and hemicholine.

The most important disease that affects the end plates of neuromuscular junctions is myasthenia gravis, characterized by muscle paralysis due to blockade of neuromuscular impulse transmission. This disease is caused by the formation of antibodies to ACh receptors on the subsynaptic membrane, accelerating the destruction of these receptors. This autoimmune disease can be triggered by viral infections, which stimulate the expression of MHC molecules, which facilitates the recognition of the antigen by the immune system. Myasthenia gravis can also occur in patients with benign thymic tumors. The formation of such autoantibodies more often occurs in individuals who are carriers of specific subtypes (DR3 and DQw 2) of MHC class II or HLA. In rare cases, myasthenia gravis is caused by genetic defects in the ACh receptor or acetylcholinesterase channels. In patients suffering from myasthenia gravis, repeated stimulation of the motor nerves will initially cause the formation of normal summed action forces in the muscles, the amplitude of which, however, will decrease due to the progressive increase in “fatigue” of neuromuscular transmission.

Another immune autoaggressive disease in which neuromuscular transmission is disrupted is Lambert-Eaton pseudomyasthenia syndrome. This condition often develops in patients with small cell lung cancer. Ca 2+ channels in the plasma membrane of tumor cells sensitize the immune system and stimulate the formation of antibodies, which also interact with the Ca 2+ channels of the end plates of neuromuscular synapses. Due to the inhibition of Ca 2+ channels, the summed muscle action potential is initially small, but then it gradually normalizes, since repeated stimulation increases the amount of Ca 2+ accumulating in the nerve endings.

Eaton-Lambert syndrome develops when the release of acetylcholine from presynaptic nerve endings is impaired.

Botulism is a consequence of impaired release of acetylcholine by the presynaptic terminal due to irreversible binding of the Clostridium botulinum toxin to it. Symptoms include severe weakness, including breathing problems, and signs of increased sympathetic tone due to blocking of parasympathetic activity: mydriasis, dry mouth, constipation, urinary retention, tachycardia, which does not happen with myasthenia gravis. EMG shows a moderate decrease in the response to low-frequency (2-3 per 1 second) nerve stimulation and an increase in the response with increasing frequency of stimulation (50 pulses/s) or after short-term (10 s) muscle work.

Drugs or toxic substances can interfere with the function of the neuromuscular junction. Cholinergic drugs, organophosphate insecticides, and most nerve gases block neuromuscular transmission by depolarizing the postsynaptic membrane due to the excessive action of acetylcholine on its receptors. Result: miosis, bronchorrhea, myasthenic weakness. Aminoglycosides and polypeptide antibiotics reduce the presynaptic release of acetylcholine and the sensitivity of the postsynaptic membrane to it. Against the background of latent myasthenia gravis, high serum concentrations of these antibiotics aggravate the neuromuscular block.

Long-term treatment with penicillamine may be accompanied by a reversible syndrome that clinically and EMG resembles myasthenia gravis. Excess magnesium (blood level 8-9 mg/dL) is fraught with the development of severe weakness, which also resembles myasthenic syndrome. Treatment includes elimination of toxic effects, intensive monitoring and, if necessary, mechanical ventilation. To reduce excess bronchial secretion, atropine 0.4-0.6 mg is prescribed orally 3 times a day. In case of poisoning with organophosphorus insecticides or nerve gas, higher doses (2-4 mg IV over 5 minutes) may be required.

Stiff person syndrome is the sudden onset of progressive rigidity of the muscles of the trunk and abdomen, and to a lesser extent, the limbs. There are no other abnormalities, including EMG. This autoimmune syndrome develops as paraneoplastic (more often with breast, lung, rectal cancer and Hodgkin's disease). Autoantibodies against several proteins associated with GABA-glycine synapses act predominantly on inhibitory neurons of the anterior horn of the spinal cord. Treatment is symptomatic. Diazepam significantly reduces muscle rigidity. The results of plasmapheresis are contradictory.

Isaacs syndrome (synonyms: neuromyotonia, armadillo syndrome) is manifested mainly by complaints about the functioning of the limbs. Myokymia appears - muscle fasciculations that look like a conglomerate of worms moving under the skin. Other complaints: carpopedal spasms, intermittent cramps, increased sweating and pseudomyotonia (impaired relaxation after a strong muscle contraction, but without the increase and decrease on the EMG typical for true myotonia). Initially it affects the peripheral nerve, since curare relieves complaints, but under general anesthesia the symptoms persist. The reason is unknown. Carbamazepine or phenytoin reduces complaints.

Myasthenia gravis and other disorders of neuromuscular impulse transmission. Part 2

L. G . Engel (A. G. Engel)

Neuromuscular transmission disorders can be genetically inherited or acquired. They are usually accompanied by severe muscle weakness and rapid fatigue when performing a particular muscle action. In such diseases, the generation of nerve impulses of sufficient amplitude in the nerve endings still occurs, but the action potential of the muscle fiber cannot spread further due to the influence of one or more specific mechanisms.

Myasthenia gravis

Definition. Myasthenia gravis ) is an acquired autoimmune disease characterized by a deficiency of acetylcholine receptors (AChRs) at the motor end plate of the nerve. The number of acetylcholine (ACh) quanta released from the nerve terminal when a nerve impulse occurs in it, and the probability of ACh release by quanta, apparently does not change, however, the number of receptors capable of capturing this ACh is reduced, resulting in a decrease in the amplitude of the potential on terminal neural plate. The response to a single quantum of ACh released by the nerve ending at rest, which is like a miniature potential of the nerve ending, is also reduced. In some cases, only the extraocular muscles are affected, in others, the disease becomes generalized. The severity of symptoms of the disease decreases after rest or taking anticholinesterase drugs. Antibodies to AChR circulating in the blood are found in 80-90% of patients, and immune complexes ( IgG and complement components) are typically deposited on the postsynaptic membrane of the motor end plate.

Clinical manifestations . The disease occurs with a frequency of 2 to 5 cases per year per 1 million population, and its prevalence is 13-64 cases per 1 million. Women are more often affected than men (ratio 6:4). The disease can begin at any age, but women usually become ill in the 3rd decade of life, and men in the 6th-7th decades. The severity of symptoms can fluctuate hourly, daily, weekly, etc. Symptoms worsen with physical effort, extreme temperatures, under the influence of a viral or other infection, menstruation, or emotional arousal. Damage to the extraocular muscles is usually bilateral, asymmetrical and, as a rule, combined with ptosis or diplopia. Involvement in the pathological process of other muscles innervated by cranial nerves leads to loss of facial expression, everting of the lips, transformation of a smile into a kind of grimace, drooping of the lower jaw, nasal regurgitation of fluids, choking when eating food and liquids, and the appearance of slurred, meager and nasal speech . Extremely rapid fatigue of the muscles of the limbs leads to difficulties when combing hair, repeatedly lifting certain objects, when climbing stairs, walking or running. Depending on the severity of the disease, shortness of breath may occur with moderate or light exertion or even at rest. This pathological muscle fatigue can be detected by simple counting tests: the patient is asked to look up without closing his eyes for 1 minute, while counting loudly from one to one hundred; also, within 1 minute, they are asked to raise their arms to shoulder level and hold them horizontally or repeatedly bend the leg deeply at the knee joint. Deep tendon reflexes are normal even in weakened muscles. Approximately 15% of patients experience atrophy of the masticatory, temporal, facial muscles, tongue muscles and, less commonly, other muscles.

Natural course of the disease. During the first month after the onset of the disease, disorders of only the oculomotor muscles appear in 40% of patients, generalized disorders - in 40%, damage to only the limbs - in 10%, only the bulbar muscles or bulbar and oculomotor muscles are involved in the pathological process - in 10% . As the disease progresses from milder to more severe, muscle weakness spreads from the oculomotor muscles to the facial muscles, to the lower bulbar muscles, to the muscles of the trunk and limbs (the sequence of muscle damage can be any). The proximal muscles of the extremities are affected to a greater extent than the distal ones, and in more advanced stages of the disease, muscle weakness becomes universal. By the end of the first year, the oculomotor muscles are affected in almost all patients. Symptoms remain only ocular in no more than 16% of patients. In almost 90% of patients in whom the disease becomes generalized, this occurs during the first year of the disease. The disease progresses particularly rapidly during the first three years, and more than half of the deaths associated with the disease occur during this period. Of course, spontaneous remissions can also be observed, but they last from several weeks to a year; longer remissions are very rare.

60% of patients with myasthenia gravis have thymic hyperplasia, and 10-15% of patients develop thymoma. A small number of patients with thymoma also develop myocarditis and/or giant cell myositis. In approximately 10% of patients, myasthenia gravis is combined with other autoimmune diseases, such as hyperthyroidism, polymyositis, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, ulcerative colitis, pemphigus, sarcoidosis, pernicious anemia and Lambert-Eaton myasthenic syndrome.

Clinical types of myasthenia. Classification of myasthenia gravis proposed Osserman , is based on the nature of the spread of the disease throughout the human body and the severity of symptoms.

Group 1 - ocular symptoms.

Group 2A - mildly expressed generalized symptoms.

Group 2B - moderately severe generalized symptoms.

Group 3 - acute fulminant symptoms.

Group 4 - late, pronounced symptoms.

The following alternative classification relates to thymoma and age at onset:

Type 1, with thymoma: the disease is usually severe, the titer of antibodies to acetylcholine receptors (AChR) in the blood is high. Connections with gender or system antigens No HLA.

Type 2, without thymoma, onset of the disease before the age of 40: the titer of antibodies to AChR in the blood is intermediate. Among the patients, women predominate; a connection with certain groups of the system is noted HLA - HLA - Al; HLA - B 8 and HLA - DRw 3 (HLA - B 12 - in Japan).

Type 3, without thymoma, onset of the disease after 40 years: the titer of antibodies to AChR in the blood is low. Among the patients, men predominate, the connection with groups of the antigen system is increased HLA - HLA - A 3, HLA - B 7 and HLA - DRw 2 (HLA -АУ - in Japan).

Antibodies to striated muscle are found in 90.5 and 45%, respectively, in types 1, 2, 3. The association with other autoimmune diseases is greatest in type 3, least in type 1.

Transient neonatal myasthenia. Circulating antibodies to AChR are found in most newborns of mothers with myasthenia gravis, but only 12% of them develop the disease. Signs of the disease appear within the first few hours after birth. These are difficulties with feeding the child, generalized muscle weakness, breathing disorders, weak cry of the child, weakness of the facial muscles, ptosis. There is no connection between the severity of the disease in the mother and the child. The disease is caused by passive transfer of AChR antibodies or adoptive transfer of immunocytes from mother to infant, or perhaps as a result of damage to AChR in the fetus by maternal antibodies, causing a temporary response in the newborn.

Immunopathogenesis. The autoimmune nature of myasthenia gravis and the pathogenetic role of antibodies to AChR have been established by a number of precise studies: 1) in animals immunized with AChR, a syndrome resembling myasthenia gravis developed; 2) circulating AChR antibodies were detected in most patients; 3) passive transmission from person to mouse has been established with IgG several characteristic signs of the disease; 4) the localization of immune complexes on the postsynaptic membrane was determined; 5) a beneficial therapeutic effect of plasmapheresis was discovered. The fact that in myasthenia gravis there is a deficiency of AChR at the end plates of nerves has been established by autoradiographic, ultrastructural and radiochemical studies usingA-bungarotoxin, a molecule of which binds to AChR with a high degree of affinity. These studies were undertaken to quantify AChR at nerve endplates. Moreover, a decrease in the number of AChRs in muscles in myasthenia gravis correlates with a decrease in the amplitude of “miniature potentials” from the end plates of nerves.

Antibodies bound to AChR end plates cause AChR failure by two main mechanisms—complement disruption and modulation. Fixation of complement and activation of the lytic phase of the complement reaction leads to focal destruction of synaptic folds and loss of AChR into the synaptic space. Modulation consists of accelerated internalization and destruction of AChRs cross-linked with antibodies. The number of AChRs decreases when the synthesis and penetration (immersion) of new AChRs into the membrane does not keep pace with the loss of AChRs. And further, lysis of synaptic folds by complement reduces the membrane surface into which new AChRs can immerse, which further increases AChR deficiency both through modulation and through complement. Some antibodies to AChRs can affect their function by blocking the binding of acetylcholine to AChRs. Blocking antibodies constitute only a small fraction of all AChR antibodies.

The fact that myasthenia gravis is often accompanied by pathology of the thymus, as well as the beneficial effect of removing the latter, indicates its participation in the pathogenesis of myasthenia gravis. It has been suggested that sensitization of lymphocytes to AChR occurs specifically in the thymus and that antigen-specific T helper cells are accordingly produced and exported from the thymus to other antibody-producing areas of the body.

Diagnostics.Diagnosis is based on a characteristic history, physical examination, anticholinesterase tests and laboratory results (electromyography, serological tests and, in some cases, microelectrode studies of neuromuscular transmission in vitro , as well as ultrastructural and cytochemical studies of end plates).

Anticholinesterase tests. When administered intravenously, edrophonium ( Edrophonium ) takes effect in a few seconds, and its effect lasts for several minutes. Its amount equal to 0.1-0.2 ml (10 mg/ml solution) is administered intravenously over 15 s. If the response does not occur within 30 s, then 0.8-0.9 ml of the drug is administered again. To assess the response, it is necessary to determine the degree of ptosis, the amount of movement of the eyeball, and the strength of the grasping movement of the hand. Side effects are also possible: fasciculation, severe facial hyperemia, lacrimation, cramping abdominal pain, nausea, vomiting, diarrhea. In patients with cardiovascular disease, edrophonium should be administered with caution, as it can cause sinus bradycardia, atrioventricular block, and sometimes cardiac arrest. These manifestations of the toxic effect of edrophonium are usually relieved with atropine; effect of intramuscularly administered neostigmine ( Neostigmine ) at a dose of 0.5-1 mg begins after 30 minutes and continues for almost 2 hours, which allows you to slowly assess the changes occurring in the body.

Electromyography (EMG). With EMG, supramaximal stimulation of the motor nerve with a frequency of 2 to 3 Hz causes in 10% or more of those examined a decrease in the amplitude of the evoked compound muscle action potential in the direction from the first to the fifth stimulation. The test is positive in almost all patients with myasthenia gravis, provided that two or more distal and two or more proximal muscles are examined. The decrease in indicators is caused by a natural decrease in the number of quanta of nervous energy released from nerve endings and a reduced amplitude of end-plate potentials, especially at the beginning of low-frequency stimulation. In myasthenia gravis, the amplitude of the endplate potentials is already reduced, which is associated with AChR deficiency, but its additional decrease during stimulation causes a blockade of neuromuscular transmission in an increasing number of endplates. The transmission defect, however, decreases for a few seconds after a 15-30 second period of maximum voluntary contraction, but becomes significant again a few minutes later. This phenomenon also reflects normally functioning presynaptic mechanisms that increase or decrease the quantal content of endplate potentials and therefore provide a safe threshold for neuromuscular transmission. Single muscle fiber electromyography allows comparison of the timing of action potentials between a pair of nearby muscle fibers in the same motor unit. In myasthenia gravis, the low amplitude and slow rise time of the endplate potential curve causes pathologically prolonged interpotential intervals and transient blockade of the generation of action potentials in some muscle fibers.

Serological tests. The test for AChR antibodies is positive in almost all patients with moderate and acute myasthenia, in 80% of patients with a mild generalized form, in 50% of patients with the ocular form of myasthenia, and only in 25% of patients in remission. The titer of these antibodies correlates quite freely with the severity of the disease, but if in a particular patient a decrease in this titer of more than 50% is maintained for 14 months or longer, then this always indicates a steady improvement in his condition. In patients with myasthenia gravis, antibodies to striated muscle are also periodically detected. The role of the latter is unknown, but their connection with thymoma is clinically confirmed.

Other diagnostic tests.Using cryostat sections, immune complexes are detected on the end plates of nerves even if circulating AChR antibodies are not detected. The most convenient and technically feasible method for confirming a suspected diagnosis is the method of determining the localization of C3. To date, light microscopy has not been able to detect immune complexes on nerve endplates in any neuromuscular disease other than myasthenia gravis. During electrophysiological studies in vitro neuromuscular transmission can differentiate between atypical cases of myasthenia gravis, Lambert-Eaton myasthenic syndrome and some congenital myasthenic syndromes.

Differential diagnosis . The differential diagnosis for myasthenia gravis usually includes neurasthenia, oculopharyngeal dystrophy, progressive external ophthalmoplegia with the absence or presence of weakness in other muscles innervated by cranial nerves or in the muscles of the extremities; intracranial space-occupying processes compressing the cranial nerves; drug-induced myasthenic syndromes and other diseases associated with impaired neuromuscular transmission. Neurasthenia is diagnosed using muscle tests and the absence of clinical abnormalities and changes in laboratory parameters characteristic of myasthenia. In myopathies involving the extraocular muscles, muscle weakness is usually stable rather than fluctuating: diplopia is a rare symptom, and muscle biopsy can reveal a clear morphological pathology; however, pharmacological and laboratory tests confirming myasthenia gravis are negative. Drug-induced and other myasthenic syndromes are discussed in the relevant sections.

Treatment. Currently, cholinesterase inhibitors, prednisone (every other day), azathioprine, thymectomy, and plasmapheresis are used to treat patients with myasthenia gravis.

Cholinesterase inhibitors are effective in all clinical forms of myasthenia gravis.

Pyridostigmine bromide (60 mg in one tablet) acts within 3-4 hours, and neostigmine bromide (15 mg tablets) - within 2-3 hours. Since pyridostigmine bromide acts further and has fewer muscarinic-like side effects than neostigmine bromide, then it is used more widely. During the day, patients are given 1/2-4 tablets of pyridostigmine bromide every 4 hours. Pyridostigmine bromide is also available in “long-term” tablets of 180 mg for use at night, as well as in the form of syrup for children and patients whose nutrition is provided through nasogastric tube. If muscarinic side effects are severe enough, atropine is prescribed 0.4-0.6 mg orally 2-3 times a day. In the postoperative period or very seriously ill patients, preparations of pyridostigmine bromide (dose 1/30 of the oral dose) or neostigmine methyl sulfate (dose of 1/25 of the oral dose) for intramuscular injections can be recommended.

Progressive muscle weakness, despite the use of ever-increasing doses of cholinesterase inhibitors, serves as a signal of the onset of a myasthenic or cholinergic crisis. Cholinergic crisis is manifested by muscarinic effects such as cramping abdominal pain, nausea, vomiting, diarrhea, miosis, increased lacrimation, increased bronchial secretion, diaphoresis and bradycardia. A crisis is more myasthenic than cholinergic if the muscarinic effects are not so obvious and if after intravenous administration of 2 mg of edrophonium muscle weakness begins to decrease rather than increase. In practice, however, it is quite difficult to distinguish between these two types of crises and excessive drug therapy aimed at eliminating a myasthenic crisis turns it into a cholinergic one. So patients with increasing respiratory, feeding, and pelvic disorders who do not respond to sufficiently high doses of anticholinesterase drugs should be switched to a drug-free treatment regimen. They should undergo tracheal intubation or tracheostomy, support breathing with a respirator, and nutrition with intravenous administration of nutritional mixtures. After a few days, drug refractoriness usually disappears.

Patients with a generalized form of the disease who do not respond adequately to moderate doses of anticholinesterase drugs must be treated differently. Thus, thymectomy increases the frequency of remissions and alleviates the symptoms of myasthenia gravis. And although there have been no correlational clinical studies of the effect of thymectomy on the course of myasthenia gravis depending on age, gender and severity of the disease, it is generally accepted that removal of the thymus gland is most effective in young women with a hyperplastic gland and high titers of antibodies in the blood. Thymoma is an absolute indication for thymectomy, as this tumor is locally quite invasive. Chest x-ray combined with slice-by-slice tomography can detect most cases of thymoma. Mediastinal CT is considered a highly sensitive screening test in this regard, but can sometimes produce false-positive results.

Taking prednisone every other day often achieves remission or significantly improves the condition in more than 50% of patients. This treatment can be considered quite safe, provided that the precautions prescribed for all patients receiving corticosteroids are observed. With an average dose of prednisone of 70 mg every other day, the patient's condition begins to improve approximately five months after the start of treatment. Once the patient's condition reaches a certain plateau, the prednisone dose should be reduced over several months to determine the minimum maintenance dose. Azathioprine in doses of 150-200 mg per day also causes remissions and significantly improves the condition in more than 50% of patients, but some of them were simultaneously treated with prednisone or underwent thymectomy. When treated with azathioprine, patients' condition improves after about 3 months. To determine the incidence of side effects of such treatment (pancytopenia, leukopenia, severe infections, hepatocellular liver damage), appropriate observations should be continued.

Plasmapheresis is indicated for severe generalized or fulminant forms of myasthenia gravis, refractory to other types of treatment. The exchange of two liters of plasma during the day leads to an objective improvement in the patient’s condition within a few days and reduces the titer of AChR antibodies in the blood. However, plasma exchange alone does not provide long-term protection compared to treatment with immunosuppressive drugs alone.

T.P. Harrison.Principles of internal medicine.Translation by Doctor of Medical Sciences A. V. Suchkova, Ph.D. N. N. Zavadenko, Ph.D. D. G. Katkovsky