Myasthenia and myasthenic syndromes. Physiological basis of disturbances in the conduction of excitation at the neuromuscular synapse List of essential medications

Synapses form the basis of intercellular communication in the nervous system. In recent years, it has been established that it is synaptic transmission that is the “weak link” in the development of pathology of the nervous system, and its disorders underlie the pathogenesis of a number of neurological and psychiatric diseases.

In particular, synaptic pathology is detected in almost all NDDs (Garden and La Spada, 2012), even before the onset of noticeable neuronal death (Kamenetz et al., 2003; Dupuis and Loeffler, 2009). Synaptic dysfunction plays a key role in the development of Alzheimer's disease, which has led to its being considered a “synaptic disease” (Selkoe, 2002). A number of works in recent years have established that in NDD, dysfunction develops not only in the central, but also in the neuromuscular synapses.

We have identified pronounced synaptic dysfunction at the level of the neuromuscular junction, as well as other disorders of the neuromuscular system in models of Alzheimer's disease and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is an NDD, which is accompanied by the death of central and peripheral motor neurons, is characterized by steady progression and leads to death. The prevalence of ALS in the world averages 2-5 cases per 100 thousand people per year. At the same time, recently there have been trends towards an increase in its incidence in all age groups. It is now generally accepted that a key factor in the pathogenesis of neuronal death in amyotrophic lateral sclerosis is the activation of apoptosis.

In electrophysiological experiments on the diaphragm of transgenic mice of the B6SJL-Tg(SOD1-G93A)dl1Gur/J line with a model of amyotrophic lateral sclerosis (ALS) at the pre-symptomatic stage of the disease, a decrease in the quantum composition and an increase in the rise time of the end plate potential, a decrease in the intensity of FM 1- loading were detected. 43 in NO and acceleration of its subsequent unloading, as well as an increase in the recycling time of synaptic vesicles in NO compared with wild-type mice. The results obtained indicate a significant disruption of the processes of neurosecretion and recycling of synaptic vesicles at the synapse. In addition, pronounced disturbances in skeletal muscle electrogenesis were found in transgenic mice with a model of ALS. Using a spectrophotometric method, it was found that in G93A mice with both symptomatic and presymptomatic stages of ALS, the concentration of H 2 O 2, one of the key reactive oxygen species, in the brain, spinal cord and the studied skeletal muscle is not significantly different from that in mice wild type. The findings expand our understanding of the pathogenetic mechanisms of ALS and other neurodegenerative diseases.

IN experimental studies It was revealed that in two animal models of AD, the f-amyloid model and transgenic mice of the B6C3- Tg(APP695)85Dbo Tg(PSENI)85Dbo) line, dysfunction of the peripheral excitable structures of the nervous system occurs. muscular system. It was found that in the P-amyloid and genetic models of AD, there is a pronounced dysfunction of the neuromuscular synapse, one of the key mechanisms in this case is a violation of the recycling parameters of synaptic vesicles in the motor nerve ending. In two models of AD, there is also a disturbance in the electrogenesis of skeletal muscle fibers, manifested in the form of a decrease in the value of the resting membrane potential. However, the mechanism of electrogenesis disorders is different - in the P-amyloid model (acute model), there is a pronounced inhibition of the sodium-potassium pump and an increase in the permeability of the muscle fiber membrane for cations due to the formation of cation-selective “amyloid” channels in the plasma membrane of muscle fibers, and in the genetic model of AD (chronic model), there is a decrease in activity and a transition to a different (lower) stationary level of work of N + /K + -ATPase and, possibly, other ion pumps of the muscle fiber membrane (Mukhamedyarov et al., 2011; Mukhamedyarov et al., 2014). One of the possible mechanisms of dysfunction of skeletal muscle fibers may be an increase in the production of reactive oxygen species, in particular hydrogen peroxide, in these cells, which was shown during research.

There is evidence of dysfunction of the neuromuscular synapse in the model of Huntington's disease - NDD, characterized by gradual onset at the age of 35-50 years and a combination of progressive choreic hyperkinesis and mental disorders. In the model of Huntington's disease on R6/1 transgenic mice, an increase in the amplitude and quantum composition of end plate potentials was revealed with unchanged parameters of spontaneous neurosecretion and the absence of disturbances in the size and dynamics of the recycling pool of synaptic vesicles. In addition, an increase in the expression of several synaptic proteins was found, in particular VAMP/synaptobrevin and SNAP-25 (Rozas et al., 2011).

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 neuromuscular 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 immune system and stimulate the formation of antibodies that also interact with Ca2 channels at 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.

1. Presynaptic disorders. Only selected disorders are considered. Eaton-Lambert myasthenic syndrome, which has more hidden manifestations, is not discussed in this section.

Botulism caused by a toxin produced by Clostridium botulinum. This disease often manifests itself as weakness of the eye muscles, followed by dysarthria, weakness of the respiratory muscles and muscles of the extremities. This diagnosis can be confirmed by information about the intake of infected food products. An increase in responses is observed with rhythmic stimulation of the nerves at high frequencies. Nerve conduction is usually not changed. Intoxication most often develops in those infants and young children whose gastrointestinal tract could be colonized by C. botulinum,

Tick paralysis is a rare disease caused by Dermacentor andersonL Neurological disorders begin with difficulty walking and balance problems, followed by ascending flaccid paralysis and areflexia. The ocular and bulbar muscles may be involved. EMG reveals a decrease in the amplitude of muscle action potentials and an increase in responses to high-frequency stimulation, especially in the acute stage. There may be some slowdown in the conduction of impulses along the motor and sensory nerves. A thorough examination of the scalp and pubic area is recommended to detect the pathogen.

Organic phosphate poisoning causes weakness mainly of the proximal muscles of the legs. Fatigue and weakness of the extraocular and bulbar muscles may occur. Muscarinic symptoms are often present (miosis, increased salivation, generalized fasciculations). The EMG is usually normal. Rhythmic nerve stimulation may reveal increased responses at high stimulation rates.

Drug-induced myasthenia. Some medications have side effect on neuromuscular transmission. Weakness usually occurs in the proximal limb musculature more than in the ocular or bulbar muscles. Drug-induced myasthenia gravis can occur when taking kanamycin, gentamicin, procainamide, primidone, and hydantoins.

2. Postsynaptic disorders: myasthenia gravis. In adults, myasthenia gravis with autoimmune disorders usually begins with intermittent and asymmetrical weakness of the extraocular and eyelid muscles, followed by weakness of the bulbar and limb muscles. Typically, clinical manifestations are unilateral or bilateral and include ptosis, dysarthria, dysphagia, proximal muscle weakness, and respiratory muscle dysfunction. When repeating movements, muscle fatigue is also observed. Muscle tone, muscle volume, reflexes, sensitive area without deviations. Diagnosis is based on clinical examination, edrophonium (tensilone) test results, single-fiber EMG, rhythmic stimulation, and serum acetylcholine receptor antibodies.

Primary myopathies

1. Polymyositis/dermatomyositis (PM/DM). Acute inflammatory myopathies usually begin with symmetrical weakness in the proximal muscles, including the muscles of the shoulder and femoral girdles. Muscle tone and volume, muscle tension reflexes are normal. There are no sensory disorders. Polymyositis usually occurs without pain. If typical skin lesions (erythematous rash in the periorbital areas, forehead or chest, and especially erythematous rash over the joints and extensor surfaces) are observed in combination with weakness, the possibility of dermatomyositis should be considered. Serum creatine kinase, aldolase, lactate dehydrogenase, and aspartate aminotransferase are often elevated. ESR is usually high. SPNV and potential amplitudes are normal. Needle EMG reveals an increase in the number of spontaneous potentials, such as fibrillations, positive sharp waves, high-frequency discharges, and small polyphasic short-duration low-amplitude motor unit potentials. Muscle biopsy reveals inflammatory changes extending to the perimysium and endomysium, combined with muscle fiber necrosis and varying degrees of muscle fiber regeneration.

3. Acute toxic myopathy. Acute alcoholic myopathy manifests as generalized symmetrical weakness. Hypermagnesemia also causes acute generalized weakness, especially in patients suffering from alcoholism and receiving excess magnesium from food. Amiodarone and L-tryptophan can cause acute myopathy. L-tryptophan can cause myalgia, weakness and eosinophilia.

4. Acute periodic paralysis is a group of primary muscle diseases that are associated with normal (normokalemic variant), elevated (hyperkalemic variant) or low potassium levels (hypokalemic variant). Hyperkalemic periodic paralysis often occurs due to stress or a carbohydrate-rich diet after intense exercise. Hyperkalemic periodic paralysis manifests itself as generalized weakness while the functions of the cranial nerves and respiratory muscles are preserved. During attacks, muscle tension reflexes are absent. The diagnosis may be suspected by evidence of intermittent weakness induced by exercise or a carbohydrate-rich diet, family history, and abnormal serum potassium levels at the time of the attack. EMG during an attack may not reveal abnormalities. Muscle biopsy reveals vacuolar myopathy, especially when drugs are given at the time of the attack. In suspicious cases with normal potassium levels, provocative tests may trigger the development of an attack.

5. Acute steroid tetraplegic myopathy often observed in patients who are prescribed high doses of steroids and drugs that block neuromuscular transmission for status asthmaticus. After relief of status asthmaticus, patients experience weakness and require mechanical ventilation. EMG reveals signs of neurogenic and myopathic disorders. The conduction of impulses along nerve fibers is not affected. Muscle biopsy with electron microscopy usually reveals loss of myosin filaments.

Diagnostics.

Diagnosis is based on identifying muscle weakness and determining the involvement of upper or lower motor neurons. After excluding damage to the upper motor neuron, it is necessary to determine the level of damage to the lower motor neuron in accordance with the algorithm presented in the figure. Often required laboratory research. The most informative test is the EMG. To confirm/exclude PM/DM, muscle biopsy is recommended. For neuropathies due to vasculitis, a nerve biopsy is indicated.

Consultations with specialists.

Patients with acute weakness neuromuscular type require hospitalization, especially with acute paralysis and suspected Guillain-Barré syndrome. If the bulbar and respiratory muscles are involved, patients need to be transferred to the intensive care unit. Patients with other neuromuscular diseases can be evaluated and treated in an outpatient setting. In most cases, help can be provided by a general practitioner, but to clarify the diagnosis, a consultation with a neurologist is required.

Myasthenia gravis is a disease of the nervous and muscular system, which is characterized by weakness and pathological fatigue of striated muscles and is not hereditary. In myasthenia gravis it is affected locomotor system at the neuromuscular junction. With this disease, the muscles of the face, then the neck, torso, lower and upper extremities are significantly affected.

Etiology, pathogenesis. Modern ideas about the mechanisms of development of myasthenia gravis are based on three fundamental scientific discoveries. In 1899, G. Oppenheim first drew attention to the connection between myasthenia gravis and tumor thymus- thymoma (80% of patients with myasthenia gravis have a tumor or hyperplasia of the thymus gland).

M. Volker in 1934 discovered that the clinical picture of myasthenia gravis has much in common with the symptoms of intoxication from curare poisoning and proposed using a curare antagonist for its treatment - the anticholinesterase drug physostigmine (a synthetic analogue of proserin).

In 1960, Strauss and co-authors found that antibodies to the tissue of the thymus gland and skeletal muscles were found in the blood of patients with myasthenia gravis. This gave reason to believe that the prerequisite for the disease is an autoimmune process, a disorder of neuromuscular transmission.

According to modern ideas Myasthenia gravis is considered a classic organ-specific, antibody-induced T-cell-dependent autoimmune disease. It is believed that as part of the autoimmune process, antibodies produced by thymocytes of the thymus gland compete with acetylcholine for the postsynaptic plate and block neuromuscular transmission. In addition, antibodies, by blocking postsynaptic receptors, directly affect not only their active centers, but also their protein component, causing accelerated degradation of the receptors. A certain role in the pathogenetic mechanisms of the block of the myoneural synapse is played by a violation of the synthesis of acetylcholine due to a defect in enzyme activity. The current literature presents five main criteria that prove that myasthenia gravis is an antibody-induced autoimmune disease. First, antibodies to acetylcholine receptors (AChR) are detected in the serum of 80-90% of patients with myasthenia gravis; secondly, these antibodies (class G) interact with AChR antigens, accumulating in the myoneural synapse; thirdly, the clinical picture of the disease is reproduced experimentally in animals by injecting them with blood serum of patients; fourthly, immunization of animals entails the induction of antibodies to AChR and the appearance of clinical symptoms of myasthenia gravis; fifthly, a decrease in the titer of antibodies to AChR often leads to an improvement in the condition of patients.

Clinic. A specific symptom of myasthenia gravis is pathological muscle fatigue that occurs after physical activity. Muscle weakness differs from ordinary paresis in that when stereotypical movements are repeated, it sharply intensifies and can reach the degree of paresis or complete paralysis. After rest, the range of movements increases.

The disease occurs in most cases in people aged 20-30 years. Women get sick 2 times more often than men. Depending on the location of clinical manifestations, myasthenia gravis is localized - with damage to the oculomotor muscles (ocular form), muscles of the tongue, larynx (bulbar form) and generalized - with damage to the muscles of the face, neck, trunk and limbs. In approximately 70% of patients, the disease begins with oculomotor disorders, in 20% - with bulbar ones.

In typical cases of the disease, the first symptoms are oculomotor disorders; patients complain of drooping eyelids and double vision. During neurological examination Ptosis is determined (Fig. 145), often asymmetric. The symptoms are dynamic: the intensity of ptosis can change throughout the day depending on physical activity. As a rule, ptosis increases in the evening; it often increases while fixing the gaze. Pupillary reactions are predominantly lively, with occasional anisocoria or wasting pupillary reactions during repeated examinations. Over time, weakness and fatigue of the facial and masticatory muscles develop. When the oculomotor, facial and masticatory muscles are involved in the pathological process, upon external examination the patient has a characteristic mask-like face, with no wrinkles, poor facial expressions, and drooping eyelids. When you smile, it only rises upper lip, in the same time underlip and the corners of the mouth remain motionless. Most often, weakness of the orbicularis oris muscle is observed, which leads to the inability to pronounce the sound “r”, labial sounds “b”, “p”. In 3% of patients, this symptom is the first manifestation of the disease. A typical complaint of patients is fatigue of the masticatory muscles when chewing solid food. In severe cases, patients should take a break while eating.

Damage to the bulbar muscle group causes dysfunction soft palate and epiglottis: patients complain of difficulty swallowing, a “nasal” tone of voice, its “attenuation,” and fatigue during a conversation. In severe cases of the disease, patients cannot swallow saliva or chew solid food. Due to impaired swallowing, aspiration pneumonia or nutritional exhaustion may develop.

In the presence of generalized forms of myasthenia, one of the most severe symptoms is weakness of the respiratory muscles. Tendon reflexes do not change. There are no pyramidal signs or pelvic disorders observed. Sensitivity is preserved.

Approximately 80% of patients with myasthenia gravis in the advanced stage of the disease are characterized by weakness and fatigue of the muscles of the limbs and trunk. As a rule, they appear later than pathological manifestations of the facial muscles and oral cavity. Most often, weakness of the muscles of the upper and lower extremities is observed with prolonged static efforts or the need to perform frequent repeated movements. Patients note weakness of the upper extremities when combing hair, washing clothes, sweeping the floor; Situations are possible when patients cannot hold a broom.

The first complaint of patients with weakness of the lower extremities, which gradually develops, is the inability to climb the steps of public transport. Increased fatigue The muscles of the pelvic girdle are manifested by a peculiar duck-like gait.

Almost half of the patients experience fatigue of the neck muscles, especially the extensor muscles, and a characteristic drooping of the head occurs.

The course of the disease is progressive, often with remission. The patient's condition may worsen after influenza and other infections or intoxications, although exacerbation may develop for no apparent reason.

A sudden sharp deterioration in the patient's condition is called myasthenic crisis. In this case, generalized muscle weakness, severe bulbar disorders, respiratory and cardiac dysfunction develop. Muscle weakness, which sometimes reaches the state of tetraplegia, is accompanied by severe autonomic disorders: tachycardia, sluggish pulse, mydriasis. In such cases, death can occur within tens of minutes.

Diagnostics, differential diagnosis. Myasthenia gravis is diagnosed based on the following clinical symptoms:

complaints of muscle weakness and fatigue, worsening in the evening and during physical activity;
early asymmetrical involvement of the extraocular muscles of the eyes in the process while maintaining pupillary reactions;
appearance of muscle weakness outside pain syndrome and sensitivity disorders;
a combination of muscle weakness with normal or sometimes brisk tendon and periosteal reflexes;
restoration or reduction of weakness under the influence of anticholine esterase drugs.

In addition to clinical symptoms, an important role in the diagnosis of myasthenia gravis is played by tests to identify pathological fatigue, pharmacological tests with proserin or kalamine, electromyography, the study of antibodies to acetylcholine receptors, CT or MRI of the mediastinal organs.

Various fatigue tests play an important role in diagnosis. To identify or increase ptosis and diplopia, it is necessary to ask the patient to look for 30 seconds without looking up or to the side. Dysarthria, a “nasal” tone of voice, can appear during a conversation; it can be provoked by asking the patient to read a text out loud. Weakness of the neck flexor muscles can be detected by asking the patient, who is lying on his back, to raise his head and look at his navel for 1 minute.

To determine the weakness of the muscles of the lower extremities, the patient is asked to do deep squats, walk on his toes or heels. In some patients, the M. Volker phenomenon can be detected. To do this, you need to repeat squeezing and unclenching your hands. This procedure causes not only weakness of the forearm muscles, but also an increase in ptosis.

Important in the diagnosis of myasthenia gravis are pharmacological tests. After intramuscular injection 1.5-2 ml of 0.05% solution of proserin or 0.5-1 ml of 0.5% solution of kalimine, there is a significant decrease and sometimes complete disappearance of all symptoms, but with their return to the original level after 2-2.5 h.

An electromyographic study is of great importance in diagnosing myasthenia gravis. During its implementation, a progressive decrease in the amplitude of the M-response is observed (by more than 10-15%) during rhythmic stimulation of the nerve with a frequency of 2-3 Hz. These changes are recorded in 85% of patients with generalized and in 10% with the ocular form of myasthenia. In patients with mild manifestations of myasthenia gravis, a decrease in amplitude is recorded with low-frequency stimulation (from 2 to 5 Hz) and is absent with high-frequency stimulation (50 Hz). Reliable results are obtained by electromyography of individual muscle fibers, which are innervated by one nerve fiber (recorded in 99% of patients with myasthenia gravis).

Most patients have antibodies to acetylcholine receptors. They are detected in 90% of patients with a generalized form of myasthenia gravis. In 30% of cases, antibodies to striated muscles are recorded. Their identification confirms the diagnosis of myasthenia gravis even in cases where antibodies to acetylcholine receptors are absent. When diagnosing thymoma, antibodies to striated muscles are detected in 80-90% of cases.

When examining patients with myasthenia gravis, it is necessary to conduct a CT or MRI of the mediastinal organs, which makes it possible to detect pathology of the thymus gland and determine further treatment tactics.

Differential diagnosis of myasthenia gravis is carried out with diseases in which the localization of the pathological process is determined in the brain stem: brain stem encephalitis, brain stem tumor, cerebrovascular accident in the vertebrobasilar vascular system, ocular form of myopathy, diabetic polyneuropathy, Miller-Fisher syndrome.

The clinical course of brainstem encephalitis is characterized by an acute onset. Focal neurological symptoms, alternating syndromes that partially or completely regress after treatment are determined. Brain tumors located in the brainstem may have a latent period for some time and manifest as muscle weakness. To determine the nature of the process, examination of the fundus, cerebrospinal fluid, and MRI data of the brain is important.

Disturbances of cerebral circulation in the system of vertebrobasilar vessels can be accompanied by fatigue of facial and masticatory muscles, which resembles myasthenia gravis.

In the ocular form of myopathy, dysfunction of the extraocular muscles also occurs: ptosis of the eyelids, which is gradually accompanied by immobility of the eyeballs. Myopathy differs from myasthenia gravis by more persistent oculomotor disturbances, lack of remission, and typical changes in the EMG. Many patients with myasthenia gravis have thymoma or thymic hyperplasia, which is not typical for the ocular form of myopathy.

When detected in patients diabetes mellitus ptosis and strabismus, it is necessary to differentiate diabetic polyneuropathy from the ocular form of myasthenia gravis. In patients with diabetes, in addition to symptoms of damage to the oculomotor nerves, as a rule, there is a loss or decrease in the Achilles and knee reflexes, and sensitivity disorders of the polyneuritic type.

The ocular form of myasthenia sometimes needs to be differentiated from one of the forms of multifocal polyneuropathy - Miller-Fisher syndrome. With the latter, in addition to ophthalmoplegia, areflexia of the Achilles and knee reflexes and ataxia occur.

Anamnestic data, the sequence of occurrence of neurological disorders and the dynamics of their reverse development are of decisive importance in carrying out differential diagnosis.

Treatment. The basic principles of treatment of myasthenia gravis are determined by the following areas:

compensation of neuromuscular transmission;
correction of autoimmune disorders;
influence on the thymus gland.

Treatment can be conservative or surgical. To compensate for disorders of neuromuscular transmission, anticholinesterase drugs are used: proserin, kalimin (mestinon), oxazil, ubretide, neuromidin, potassium preparations and spironolactones.

Prozerin belongs to short-acting drugs. The duration of the clinical effect when used is 2-3 hours. Patented tablets contain 15 mg of proserine. For mild forms of the disease, the average daily dose is 1-2 tablets every 6-8 hours. The drug is taken to increase muscle strength in advance of anticipated physical activity or before meals. In severe cases of the disease, it is advisable to use prozerin parenterally. In particular, if swallowing function is impaired, 1 ml of 0.05% proserin solution is prescribed subcutaneously 2-3 times a day or 1 ml intravenously.

Kalimin (mestinon) is used in tablet form. One tablet contains 60 mg of kalimine, equivalent to a standard tablet of proserine (15 mg). The duration of action of mestinon is 7-8 hours. The drug is used 3 times a day. Kalimin acts selectively on the cranial muscles, so it is especially indicated for ocular and bulbar forms of myasthenia. The drug is low-toxic; in severe cases of the disease it can be combined with proserin.

Oxazil is prescribed 0.005 g orally. The therapeutic effect occurs after 2 hours and lasts for 4-8 hours. The drug acts primarily on skeletal muscles.

Ubretide is a long-acting anticholinesterase drug (up to 24 hours). Available in tablets of 5-10 mg and ampoules of 1 ml. Given the pronounced cholinergic effect, treatment begins with a small dose (0.5 ml) subcutaneously, then switches to oral administration of the drug 5 mg 1-2 times a day.

Neuromidin (amiridin) is available in 20 mg tablets. Its effect is weaker than Kalimina. But our experience with the use of amiridine indicates that it is effective in the ocular form of myasthenia gravis.

Anticholinesterase therapy is indicated for all patients with myasthenia gravis. Pregnancy is not a contraindication to its use.

The introduction of potassium salts and agents that promote the accumulation of potassium in the body also improves synaptic conduction. In addition, they enhance the effect of anticholinesterase drugs, which makes it possible to reduce the daily dose of the latter. The effective dose of potassium chloride is 2-3 g per day, veroshpiron is 100-200 mg throughout the day. Potassium preparations and spirolactones are recommended for use at all stages of treatment, especially during exacerbation of the process.

Correction of autoimmune disorders is carried out with the help of glucocorticoid drugs, cytostatics and plasmapheresis.

Treatment with glucocorticoid drugs is indicated for ineffective thymectomy, the presence of contraindications to thymectomy, and also as preoperative preparation for patients with impaired vital functions.

Recently, during treatment autoimmune diseases Pulse therapy with glucocorticoids has been successfully used. Currently, the use of solyumedrol (metipred) at a dose of 250-500 mg daily for 3-5 days is one of the most effective treatment regimens. This scheme allows you to achieve a more lasting effect, and also promotes an early transition to the remission stage. In most patients, after administration of solumedrol, compensation of myasthenic symptoms occurs and there is no need for further oral use of glucocorticoids. However, in some cases it is necessary to transfer patients to medium oral doses of prednisolone every other day (40-60 mg).

In addition to hormonal pulse therapy, there are several treatment regimens with prednisolone. The most common is an alternating dosing regimen. Prednisolone is prescribed at the rate of 0.8-1.2 mg per 1 kg of body weight (the optimal dose is 60-80 mg). The drug is taken in the morning on an empty stomach 1 time every 2 days. The above doses are used until a noticeable clinical effect is achieved. As the patient's condition improves, the dose of prednisolone is reduced gradually - 1/4 to 1/2 tablet per dose. The maintenance dose is variable and is approximately 5-20 mg and is maintained for many years. Treatment with prednisolone is combined with the use of anticholinesterase drugs, most often with proserin, which is prescribed on a “non-prednisolone” day.

However, in clinical practice in some cases, a paradoxical reaction to large doses of prednisolone is observed, which is manifested by increased muscle weakness. In such cases, it is advisable to use another treatment regimen: gradually increasing the dose - treatment begins with a dose of 10 mg of prednisolone every other day, then it is increased by 10 mg every week to 60-80 mg every other day. After achieving remission, the dose of the drug is gradually reduced by 5 mg and brought to maintenance.

The anabolic hormone retabolil is used simultaneously with glucocorticoids. It is prescribed intramuscularly at 50 mg once every 3 days. After 5-6 injections and achievement of a therapeutic effect, the intervals between injections are increased to 5, 7, 10, 15, 20, 25 days. To achieve a lasting effect, it is necessary to carry out maintenance therapy for a long time - make 1 injection once a month for several years.

Currently, cytostatic immunosuppressants: azathioprine, cyclophosphamide and methotrexate are widely used in the treatment of patients with myasthenia gravis. Their mechanism of action is different. Azathioprine blocks the synthesis of immunoglobulins and reduces the titer of antibodies to acetylcholine receptors, while cyclophosphamide and methotrexate reduce the number of B-lymphocytes and inhibit the antibody response. Cytostatics are prescribed in cases where there is resistance to glucocorticosteroids and certain contraindications to their use. Azathioprine is prescribed daily in increasing doses - from 50 to 150 - 200 mg per day. While taking azathioprine, you can reduce the dose of steroids much faster. The clinical effect appears after 1-12 weeks and reaches a maximum after 1 year or more from the start of treatment.

Cyclophosphamide is used intravenously at a dose of 100-200 mg for 10-12 days, and then the patient is transferred to taking azathioprine daily or every other day for 3-6 months. The clinical effect occurs with the administration of cyclophosphamide also after 1-12 weeks from the start of treatment.

Methotrexate is used intramuscularly at 0.02-0.08 mg 2 times a week for 2-4 weeks or intravenously at 25-50 mg 2 times a week.

A combined treatment regimen for patients with glucocorticoids and cytostatics is effective. Treatment begins from intravenous administration cyclophosphamide at a dose of 200 mg every other day for 10 days, followed by azathioprine at a dose of 2 mg/kg 2 times a day for 3 months. The administration of cyclophosphamide is alternated with by mouth prednisone. The initial dose of prednisolone is 60-90 mg. When the effect is achieved, the dose of prednisolone is reduced by 5 mg after 3-5 doses.

Therapy with immunosuppressants should be carried out under the control of blood and urine parameters, biochemical parameters liver functions.

Recently, plasmapheresis has been widely used to treat patients with myasthenia gravis. The main indications for plasmapheresis: myasthenic crisis; acute course of myasthenia; initial stage steroid therapy due to possible exacerbation of the disease.

As additional medicinal products drugs may be used that improve metabolic processes in muscle tissue. These include primarily adrenergic agonists, in particular ephedrine, calcium preparations, amino acids (glutamic acid, methionine, phytin), tocopherol acetate, B vitamins. Extracts of schisandra, ginseng, etc. can be used as tonics.

It should be cautioned that some medicines contraindicated in patients with myasthenia gravis. These include muscle relaxants; tranquilizers (benzodiazepine derivatives - sibazon, etc.); antiarrhythmic drugs that reduce the excitability of muscle membranes and possibly block neuromuscular conduction (quinine, quinidine, procainamide, etc.); antibiotics of the aminoglycoside group (gentamicin sulfate, kanamycin, streptomycin, neomycin sulfate and polymyxin), which inhibit the release of acetylcholine; morphine and barbiturates, which should be used with great caution.

Effects on the thymus gland are considered radical methods of treatment. This is surgery or radiation therapy. Improvement in condition or stable remission is observed on average in 70% of operated patients. The early timing of surgical intervention is important (in the first year of the disease). Surgical treatment - thymectomy - is carried out in the presence of thymoma, a generalized form of myasthenia with impaired function of voice formation, swallowing and breathing, in severe ocular and bulbar forms, and in the absence of effect from conservative therapy. Surgical treatment is not recommended for persons over 70 years of age or with severe somatic diseases.

Radiation therapy of the thymus gland also has a good effect. Remission of varying severity is observed in more than 50% of cases. This type of treatment is indicated for elderly and senile patients; patients whose thymoma was removed but retained thymus; as preoperative preparation.

It is advisable to carry out radiation therapy from two parasternal fields at a total dose to the irradiation site of up to 40 Gy (4000 rad).

Complications. A severe complication of myasthenia gravis is crisis conditions, which are characterized by the appearance of breathing and swallowing disorders. Myasthenic and cholinergic crises are known. With insufficient administration of anticholinesterase drugs, patients may develop myasthenic crisis - generalized weakness of skeletal and visceral muscles, bulbar disorders, and respiratory dysfunction. In such cases, proserin 1-2 ml of a 0.05% solution in 20 ml of a 40% glucose solution or intramuscular ubretide - 1 ml (0.5 mg) is urgently administered intravenously. It should be remembered that progressive and life-threatening weakness of the respiratory muscles can occur despite the administration of the optimal dose of proserin. In this case, there is a need for tracheostomy, artificial or mechanical ventilation. Plasmapheresis is also advisable.

In the case when the patient’s condition does not improve after the administration of proserin or plasmapheresis, it should be assumed that the patient’s crisis is of a different nature. It is necessary to remember the possibility of developing a cholinergic crisis, the mechanism of which is associated with an overdose of anticholinesterase drugs. Clinical signs of a cholinergic crisis are fascicular muscle twitching, convulsions, bradycardia, drooling, sweating, abdominal pain, fear of death, and stupor. The main method of treating cholinergic crisis is the abolition of anticholinesterase drugs, the administration of atropine sulfate - 0.5-1 ml of a 0.1% solution intravenously or subcutaneously. In severe cases, the cholinesterase reactivator dipyroxil is prescribed - 1 ml of a 15% solution intramuscularly. Repeated administration is carried out no earlier than after 24 hours.

Myasthenic syndromes. In terms of clinical manifestations, they resemble the picture of myasthenia gravis, but differ from it in the uniqueness of the disruption of synaptic transmission and the specificity of the myographic picture. Myasthenic syndromes are divided into several groups:

associated with impaired release of acetylcholine from presynaptic spaces (with bronchogenic carcinoma, thyrotoxicosis);
associated with impaired formation of acetylcholine in the presence of peripheral motor neuron damage;
caused by rapid blocking of neuromuscular transmission during myotonia;
associated with congenital neuromuscular disorders (myopathies with a myasthenic component);
against the background of tumor and inflammatory processes stem localization (stem arachnoencephalitis, brain stem tumor).

The most common is myasthenic Lambert-Eaton syndrome, which is determined in bronchogenic carcinoma, as well as cancer of the stomach and rectum.

Myasthenic syndrome may precede clinical manifestations of cancer. Muscle weakness, atrophy, decreased deep reflexes, and pathological fatigue are noted. Facial muscles are rarely affected. The effect of using anticholinesterase drugs is insignificant. An electromyographic study reveals differences from myasthenia gravis: when performing rhythmic stimulation, the amplitude of the first response is low, in the case of repeated stimulation it constantly increases (the phenomenon of working in). An increase in the amplitude of muscle potentials is also observed after physical exercise.

In neurological practice, myasthenic syndrome is also often observed with brain stem arachnoencephalitis, a tumor of the brain stem. In these pathological conditions, the reticular formation suffers, there is a mismatch in the actions of different muscle groups that take part in the motor act, and pathological muscle fatigue occurs. With a tumor located in the brainstem, myasthenic syndrome may also precede the clinical picture of a space-occupying process.