Can childhood myasthenia go away? Myasthenia in children

is an autoimmune disease that causes muscle weakness due to disruption of neuromuscular transmission. Most often, the functioning of the eye muscles, facial and chewing muscles, and sometimes the respiratory muscles are disrupted. This determines the symptoms characteristic of myasthenia: drooping lower eyelid, nasal voice, swallowing and chewing disorders. The diagnosis of myasthenia gravis is established after a proserine test and a blood test for the presence of antibodies to receptors of the postsynaptic membrane. Specific treatment for myasthenia gravis involves the use of anticholinesterase drugs such as ambenonium chloride or pyridostigmine. These drugs restore neuromuscular transmission.

General information

Myasthenia (or false/asthenic bulbar palsy, or Erb-Goldflam disease) is a disease whose main manifestation is rapid (painfully rapid) muscle fatigue. Myasthenia gravis is an absolutely classic autoimmune disease in which cells of the immune system, for one reason or another, destroy other cells of their own body. This phenomenon can be considered a normal immune reaction, only it is directed not at foreign cells, but at one’s own.

Pathological muscle fatigue was described by clinicians in the mid-16th century. Since then, the incidence of myasthenia gravis has been growing rapidly and is detected in 6-7 people per 100 thousand population. Women suffer from myasthenia gravis three times more often than men. The largest number of cases of the disease occurs in people aged 20 to 40 years, although the disease can develop at any age or be congenital.

Causes of myasthenia gravis

Congenital myasthenia gravis is the result of a gene mutation that prevents neuromuscular junctions from functioning normally (such synapses are like “adapters” that allow the nerve to communicate with the muscle). Acquired myasthenia is more common than congenital myasthenia, but is easier to treat. There are several factors that, under certain conditions, can cause the development of myasthenia gravis. Most often, pathological muscle fatigue is formed against the background of tumors and benign hyperplasia (tissue proliferation) of the thymus gland - thymomegaly. Less commonly, the disease is caused by other autoimmune pathologies, for example, dermatomyositis or scleroderma.

Enough cases have been described of detecting myasthenic muscle weakness in patients with cancer, for example, with tumors of the genital organs (ovaries, prostate), less often - lungs, liver, etc.

As already mentioned, myasthenia gravis is a disease of an autoimmune nature. The mechanism of development of the disease is based on the body’s production of antibodies to receptor proteins that are located on the postsynaptic membrane of synapses that carry out neuromuscular transmission.

Schematically, this can be described as follows: the process of a neuron has a permeable membrane through which specific substances - mediators - can penetrate. They are needed to transmit impulses from a nerve cell to a muscle cell, which has receptors. The latter on muscle cells lose the ability to bind the mediator acetylcholine, and neuromuscular transmission becomes significantly more difficult. This is exactly what happens in myasthenia gravis: antibodies destroy receptors on the “other side” of the contact between nerve and muscle.

Symptoms of myasthenia gravis

Myasthenia gravis is called “false bulbar palsy” due to the fact that the symptoms of these two pathologies are really similar. Bulbar palsy is damage to the nuclei of three cranial nerves: glossopharyngeal, vagus and hypoglossal. All these nuclei are located in the medulla oblongata and their damage is extremely dangerous. With both bulbar palsy and myasthenia gravis, weakness of the masticatory, pharyngeal and facial muscles occurs. As a result, this leads to the most formidable manifestation - dysphagia, that is, difficulty swallowing. The pathological process in myasthenia gravis, as a rule, first affects the muscles of the face and eyes, then the lips, pharynx and tongue. With prolonged progression of the disease, weakness of the respiratory muscles and neck muscles develops. Depending on which muscle fiber groups are affected, symptoms can be combined in different ways. There are also universal signs of myasthenia gravis: changes in the severity of symptoms during the day; deterioration after prolonged muscle strain.

In the ocular form of myasthenia, the disease affects only the extraocular muscles, the orbicularis oculi muscle, and the muscle that lifts the upper eyelid. As a result, the main manifestations will be: double vision, strabismus, difficulty focusing; inability to look for a long time at objects located very far or very close. In addition, a characteristic symptom is almost always present - ptosis or drooping of the upper eyelid. The peculiarity of this symptom in myasthenia gravis is that it appears or intensifies in the evening. In the morning it may not be there at all.

Pathological fatigue of the facial, chewing muscles and muscles responsible for speech leads to changes in voice, difficulties with eating and speaking. The voice of patients with myasthenia gravis becomes dull, “nasal” (such speech sounds approximately the same as if a person simply spoke while holding his nose). At the same time, speaking is very difficult: a short conversation can tire the patient so much that he will need several hours to recover. The same applies to weakness of the masticatory muscles. Chewing solid foods can be physically overwhelming for a person with myasthenia gravis. Patients always try to clearly plan their meal times in order to eat at the moment of maximum effect of the medications they are taking. Even during periods of relative improvement in health, patients prefer to eat in the first half of the day, since symptoms intensify in the evening.

Damage to the muscles of the pharynx is a more dangerous condition. Here the problem, on the contrary, is the inability to take liquid food. When trying to drink something, patients often choke, and this can cause liquid to enter the respiratory tract and cause the development of aspiration pneumonia.

All the described symptoms noticeably intensify after loading one or another muscle group. For example, talking for a long time can cause even greater weakness, and chewing hard foods often leads to additional deterioration in the functioning of the masticatory muscles.

And finally, a few words about the most dangerous form of myasthenia – generalized. It is this that ensures a stable 1% mortality rate among patients with this pathology (over the past 50 years, the mortality rate has decreased from 35% to 1%). The generalized form may be manifested by weakness of the respiratory muscles. The respiratory disorder that occurs for this reason leads to acute hypoxia and death if the patient is not provided with timely assistance.

Myasthenia gravis progresses steadily over time. The rate of deterioration can vary significantly between patients, and there may even be a temporary cessation of disease progression (however, this is quite rare). Remissions are possible: as a rule, they occur spontaneously and end the same way - “on their own.” Exacerbations of myasthenia gravis can be episodic or long-term. The first option is called myasthenic crisis, and the second is called myasthenic condition. During a crisis, the symptoms pass quite quickly and completely, that is, during remission no residual effects are observed. Myasthenic condition is a long-term exacerbation with the presence of all the symptoms, which, however, do not progress. This condition may continue for several years.

Diagnosis of myasthenia gravis

The most revealing test for myasthenia gravis, which can give a neurologist a lot of information about the disease, is the proserine test. Prozerin blocks the work of the enzyme that breaks down acetylcholine (transmitter) in the synapse space. Thus, the amount of mediator increases. Prozerin has a very powerful, but short-term effect, so this drug is almost never used for treatment, but in the process of diagnosing myasthenia gravis, prozerin is necessary. Several studies are being conducted using the latter. First, the patient is examined to assess the condition of the muscles before the test. After this, proserin is injected subcutaneously. The next stage of the study takes place 30-40 minutes after taking the drug. The doctor re-examines the patient, thereby determining the body’s reaction.

In addition, a similar scheme is used for electromyography - recording the electrical activity of muscles. EMG is performed twice: before the administration of proserin and an hour after it. The test allows you to determine whether the problem is actually a disruption of neuromuscular transmission or whether the function of an isolated muscle or nerve is impaired. If even after EMG there are still doubts about the nature of the disease, it may be necessary to conduct a series of studies of the conductivity of nerves (electroneurography).

It is important to test your blood for the presence of specific antibodies. Their detection is a sufficient reason for diagnosing myasthenia gravis. If necessary, a biochemical blood test is performed (according to individual indications).

Computed tomography of the mediastinal organs can provide valuable information. Due to the fact that a large percentage of cases of myasthenia gravis can be associated with space-occupying processes in the thymus gland, CT scans of the mediastinum are performed quite often in such patients.

In the process of diagnosing myasthenia gravis, it is necessary to exclude all other options - diseases that have similar symptoms. First of all, this is, of course, the bulbar syndrome already described above. In addition, differential diagnosis is carried out with any inflammatory diseases (encephalitis, meningitis) and tumor formations in the brain stem (

In cases of severe disease and rapid progression of the disease, drugs that suppress the immune response are prescribed. As a rule, glucocorticoids are used, less often - classical immunosuppressants. When selecting steroids, you should always exercise extreme caution. For patients with myasthenia gravis, drugs containing fluoride are contraindicated, so the range of drugs to choose from is not very large. All patients with myasthenia gravis over 69 years of age undergo removal of the thymus gland. This method is also used when a volumetric process is detected in the thymus and in the case of myasthenia gravis that is resistant to treatment.

Drugs for symptomatic treatment are selected individually, based on the characteristics of each patient. A person with myasthenia gravis must follow certain rules in their lifestyle to speed up recovery or prolong remission. It is not recommended to spend too much time in the sun or undergo excessive physical activity. Before you start taking any medication yourself, consulting with your doctor is absolutely necessary. Some medications are contraindicated for myasthenia gravis. For example, taking certain antibiotics, diuretics, sedatives and medications containing magnesium - the latter can significantly worsen the patient's condition.

Forecast and prevention of myasthenia gravis

The prognosis for myasthenia gravis depends on a lot of factors: the form, time of onset, type of course, conditions, gender, age, quality or presence/absence of treatment, etc. The ocular form of myasthenia is the easiest, the most severe is the generalized form. At the moment, with strict adherence to the doctor’s recommendations, almost all patients have a favorable prognosis.

Since myasthenia gravis is a chronic disease, most often patients are forced to constantly take treatment (in courses or continuously) to maintain good health, but their quality of life does not suffer very much from this. It is very important to diagnose myasthenia gravis in a timely manner and stop its progression before irreversible changes occur.

A.Etiology. With myasthenia gravis, neuromuscular transmission is disrupted; The disease is most often based on immune damage. There are three clinical forms of myasthenia gravis.

1. Neonatal myasthenia, appears to result from passive transfer of antibodies (IgG) from a mother with myasthenia gravis. Symptoms are severe but transient.

2. Congenital myasthenia may appear in utero (weak fetal movements), during the newborn period, or during the first few years of life. The mothers of the patients do not suffer from myasthenia gravis. Symptoms are less pronounced, but more persistent than with neonatal myasthenia.

3. Juvenile myasthenia occurs in children of any age and is manifested by ptosis, double vision and other bulbar symptoms, and muscle weakness.

B.Diagnostics

1. One of the main methods is tests with AChE inhibitors. Edrophonium chloride is administered at a dose of 0.2 mg/kg IV, maximum 10 mg. Since it has a short-term effect (less than 5 minutes) and causes pronounced cholinergic side effects, neostigmine, 0.04 mg/kg IM, is administered instead to newborns and sometimes older children. The effect of neostigmine occurs within 10 minutes, reaching a peak after 30 minutes. In both cases, monitor the heart rhythm and blood pressure; if side effects occur, atropine is administered in a single dose of 0.01 mg/kg (maximum total dose - 0.4 mg).

2. EMG reveals a decrease in the amplitude of the muscle response with repeated stimulation of the nerve.

IN.Treatment

1. Neonatal myasthenia

A.Maintenance therapy limited while breathing and swallowing are maintained.

b. For swallowing and breathing problems, neostigmine is used intramuscularly or orally. The dose for intramuscular injection is 0.05-0.3 mg/kg, the dose for oral administration is 10 times higher. The drug is administered every 1-12 hours, depending on breathing and the strength of the cry. IM injections are made 20 minutes before feeding.

V. If AChE inhibitors are ineffective, plasma exchange or exchange transfusion is used. There is information about the successful use of intravenous infusion of immunoglobulin.

2. Congenital myasthenia. In newborns, treatment is the same as for neonatal myasthenia. The effectiveness of plasmapheresis and exchange blood transfusion is questionable.

3. Juvenile myasthenia

A. The basis of treatment is AChE inhibitors. They are used both for long-term treatment and for emergency conditions (acute respiratory failure). The initial dose of neostigmine is 0.3-0.5 mg/kg orally 3 times a day, pyridostigmine bromide is 1 mg/kg orally 3 times a day. Then the dose and frequency of administration are increased in accordance with the severity and duration of the effect. You can prescribe long-acting pyridostigmine tablets containing 180 mg of the drug.

b. If AChE inhibitors are ineffective even at high doses, prednisone is prescribed. The initial dose is 0.5-1 mg/kg every other day, subsequently it is increased by 0.2 mg/kg until the effect is achieved. The maximum dose is 60 mg/kg. Then the drug is gradually withdrawn.

V. Thymectomy is indicated when other treatment methods are unsuccessful, as well as in cases where long-term daily use of large doses of corticosteroids is required. Thymoma is rare in children.

G. In severe cases, plasmapheresis is used for temporary relief.

4. With an overdose of AChE inhibitors, muscle weakness increases (cholinergic crisis). Systemic cholinergic effects and worsening symptoms in the edrophonium test distinguish a cholinergic crisis from a myasthenic crisis. The drug of choice for the treatment of cholinergic crisis is atropine, 0.4 mg IV.

J. Gref (ed.) "Pediatrics", Moscow, "Practice", 1997

Catad_tema Diseases of the nervous system in children - articles

ICD 10: G70

Year of approval (revision frequency): 2016 (reviewed every 3 years)

ID: KR366

Professional associations:

• Union of Pediatricians of Russia

Approved

Union of Pediatricians of Russia

Agreed

Scientific Council of the Ministry of Health of the Russian Federation __ __________201_

GCS - glucocorticosteroids

Terms and definitions

New and narrowly focused professional terms are not used in these clinical guidelines.

1. Brief information

1.1 Definition

Myasthenia gravis is an autoimmune disease characterized by impaired neuromuscular transmission and manifested by weakness and pathological fatigue of skeletal (striated) muscles.

1.2 Etiology and pathogenesis

According to modern concepts, the basis of the pathogenesis of myasthenia gravis is an autoimmune reaction caused by the binding of acetylcholine receptors (AChRs) by antibodies to the postsynaptic membranes of striated muscles. The number of these receptors is significantly reduced by these autoantibodies. In some cases, with autoimmune myasthenia gravis (MG), antibodies (AB) to AChR are not detected, and this form is called seronegative myasthenia gravis (SN-MG). The term “seronegative” is inaccurate in relation to a group of patients, including children, who have IgG class antibodies to muscle specific receptor tyrosine kinase (MrT). This form is called MuSK-MG. Although convincing evidence of the pathogenicity of AT AChR has been obtained, the pathogenetic role of AT MuSC remains unclear. Other antibodies, the role of which has not been established, may also be detected, including titin, ryanodine receptors, and the intracellular AChR-associated protein rapsyn.

The mechanism that triggers AT production remains unknown. The role of the thymus gland is indicated by the combination of AChR and lymphoid hyperplasia and thymic tumors, as well as the effectiveness of thymectomy. In MuSC-MG, if any are detected, then only minor histological changes in the thymus are detected. The presence of a genetic predisposition is indicated by the relatively frequently observed clinical and electromyographic (EMG) symptoms in the patient’s relatives and the frequent occurrence of certain groups of antigens of the main human histocompatibility complex (HLA).

There is a combination with other autoimmune disorders, especially with thyroid pathology (hyper- or hypothyroidism), rheumatoid arthritis, lupus erythematosus and diabetes. According to some researchers, malignant tumors were observed in 5% of children.

1.3 Epidemiology

Myasthenia gravis is a relatively rare disease, although there is ample evidence to believe that it is observed much more often than previously thought. Persons with the HLA-B3, HLA-B8, HLA-DW3 phenotype are most predisposed to the disease. The prevalence of myasthenia gravis is 0.5 - 5 cases per 100 thousand population, but currently there is a tendency to increase the number of patients and is 10 - 24 cases per 100 thousand population. Myasthenia gravis can debut at any age, from early childhood (more often in girls and adolescence) to old age. Children and adolescents under 17 years of age account for 9-15% of patients with myasthenia gravis. In childhood, the juvenile form of myasthenia gravis is more common. Approximately 5-20% of infants (according to various sources) born to mothers with myasthenia gravis develop transient neonatal myasthenia (TNM), caused by the transfer of antibodies to acetylcholine receptors (AChR) from the mother across the placental barrier. The highest incidence is observed in 2 age categories: 20-40 years (during this period women are more often affected) and 65-75 years (during this period men and women are affected equally often). The average age of onset of the disease in women is 26 years, in men - 31 years.

1.4 Coding according to ICD-10

G70 – Myasthenia gravis and other neuromuscular junction disorders: excluded: botulism (A05.1), transient neonatal Myasthenia gravis (P94.0)

G70.0 – Myasthenia gravis

G70.1 - Toxic disorders of the neuromuscular junction

G70.2 - Congenital or acquired myasthenia gravis

G70.8 - Other neuromuscular junction disorders

G70.9 - Neuromuscular junction disorder, unspecified

1.5 Examples of diagnoses

• Myasthenia gravis, generalized form, progressive course, moderate severity, sufficient compensation against the background of ACEP.
• Myasthenia gravis, local (ocular) form, stationary course, mild severity, good compensation for ACEP.
• Myasthenia gravis, a generalized form with respiratory disorders, a progressive severe course with insufficient compensation for ACEP.

1.6 Classification

There are several classifications of myasthenia gravis. The most common classification in the world is according to Osserman (adopted as international in 1959 in Los Angeles, modified in 1971 by Osserman and Jenkin).

Generalized myasthenia:

• Neonatal myasthenia gravis
• Congenital myasthenia
• Benign with ophthalmoparesis or ophthalmoplegia
• Family nursery
• Juvenile myasthenia

Ocular myasthenia:

• Youth
• Adult

V.S. Lobzin in 1960 A classification of myasthenia gravis according to the course of the pathological process has been proposed:

1 – acute onset with rapid development of the symptom complex and subsequent slow progression,

2 – acute onset, longer (from 3 months to 1 year) development of the syndrome, course with remissions, but steady progression,

3 – gradual onset, slow development over several years and subsequent slowly progressive course,

4 – start with a limited muscle group and slow progression.

In 1965 A.G. Panov, L.V. Dovgel and V.S. Lobzin developed a classification of myasthenia gravis according to the localization of the pathological process, taking into account the disturbance of vital functions (impaired breathing and cardiac activity):

1 - generalized:

a) without disturbance of vital functions, b) with disturbance of breathing and cardiac activity;

2 - local:

a) facial form (ocular, pharyngeal-facial), b) musculoskeletal form: without breathing problems and with breathing problems.

The most convenient classification for a practicing physician is the one proposed in 1965 by B.M. Hechtom. It takes into account the nature of the course of the disease, the degree of generalization of the myasthenic process, the severity of movement disorders and the degree of their compensation against the background of acetylcholinesterase inhibitors (AChE), which helps to formulate a diagnosis quite completely and accurately.

According to the nature of the flow:

1. Myasthenic episodes (one-time or remitting course) – transient movement disorders with complete regression (10-12%).

2. Myasthenic conditions (i.e. stationary course) - a stationary non-progressive form over many years (13%).

3. Progressive course – steady progression of the disease (50-48%).

4. Malignant form – acute onset and rapid increase in muscle dysfunction (25%).

Forms transform into each other.

By localization:

– local (limited) processes: ocular, bulbar, facial, cranial, trunk;

– generalized processes: generalized without bulbar disorders, generalized and generalized with breathing disorders.

According to the severity of movement disorders:

Moderate

Heavy

According to the degree of compensation of motor disorders against the background of acetylcholinesterase inhibitors (AChEIs):

Sufficient

Insufficient (bad).

2. Diagnostics

2.1 Complaints and anamnesis

When collecting anamnesis and complaints, attention is paid to the variability of symptoms during the day, their connection with the load, the presence of partial or complete remissions, reversibility of symptoms while taking AChE inhibitors (for the duration of their action) and against the background of adequate immunosuppressive therapy.

2.2 Physical examination

A clinical examination should include a study of the general neurological status, as well as checking the strength of the voluntary muscles of the face, neck, trunk and limbs before and after exercise (strength assessment in points, where 0 is no strength, 5 is the strength of a given muscle group in a healthy person). One of the most important clinical tests for diagnosing myasthenia gravis is the presence of pathological muscle fatigue syndrome: an increase in symptoms after exercise. For example, an increase in ptosis, oculomotor disturbances during gaze fixation, after squinting; decrease in strength in certain muscle groups after repeated active movements in the limb under study, squats or walking; the appearance or increase in speech disorders when counting, reading aloud, etc. In this case, no symptoms of organic damage to the nervous and neuromuscular system are detected (in the absence of concomitant diseases): there are no disorders in the reflex and coordination spheres, sensitivity is preserved, in typical cases there is no muscle atrophy, muscle tone is preserved.

Juvenile autoimmune myasthenia gravis (JMG)

Symptoms of the disease can develop at any age over one year, but most often appear in girls during adolescence. The onset of the disease may be gradual or sudden.

The clinical picture is characterized by:

• damage to the extraocular muscles with diplopia, ophthalmoplegia and ptosis (can be symmetrical, asymmetrical or unilateral),
• weakness of the facial muscles (especially the orbicularis oculi muscle),
• weakness of the proximal limbs,
• damage to the respiratory and oropharyngeal muscles,
• deep tendon reflexes are preserved.

When examining children with developed respiratory failure in the absence of pulmonary pathology, it is necessary to take into account the possibility of JMG, even if there are no other symptoms of this disease.

Initially, muscle strength may be normal or nearly normal, and muscle strength should therefore be assessed before and after exercise.

The incidence of cases in which involvement is limited to the extraocular muscles only (ocular myasthenia gravis) varies widely among different publications, but is probably 20–50%, and up to 80% in young children in China. MuSK-MG is more common in women; the clinical picture is dominated by weakness of the oculomotor and cranial muscles, and frequent respiratory crises are noted. The differences between MuSK-MG and AChR-MG remain to be elucidated.

Transient neonatal form (myasthenia gravis of the newborn y)

Clinical manifestations include:

• general muscle hypotension,
• faint cry
• difficulty breathing and sucking,
• possible development of ptosis,
• amymia, oculomotor disorders,
• swallowing disorders, decreased deep reflexes.

Congenital myasthenic syndromes are presented in more detail in Appendix D1.

Transient myasthenic syndrome, which manifests itself in such children in the first days of life and lasts for 1-1.5 months, is caused by the transfer of antibodies to AChR from the mother through the placental barrier.

• concomitant diseases, and are a hallmark of the condition now called IUD with episodic apnea).

Thus, the difference between all the symptoms of myasthenia gravis is their dynamism during the day, intensification after exercise, reversibility or a decrease in their severity after rest.

Myasthenic crisis , in which, for various reasons, there is a sharp deterioration in the condition with disruption of vital functions. The molecular basis of myasthenic crisis is probably a sharp decrease in the number of functioning AChRs due to a massive attack by their autoantibodies. Often, myasthenic crisis is provoked by a bronchopulmonary infection, and in some cases, pneumonia develops against the background of the crisis, and then breathing problems can be of a mixed nature.

Myasthenic crisis can be differentiated from other severe conditions accompanied by respiratory disorders by the presence of:

• bulbar syndrome,
• hypomimia,
• ptosis,
• asymmetric external ophthalmoparesis,
• weakness and fatigue of the muscles of the limbs and neck (decreasing in response to the administration of AChE inhibitors).

It is necessary to distinguish myasthenic crisis from cholinergic crisis (Appendix D2), which develops with an excessive dose of AChE inhibitors. Common symptoms of crises are severe weakness of voluntary muscles with respiratory failure and bulbar syndrome, psychomotor agitation and impaired consciousness (stupor, coma).

Mixed (myasthenic + cholinergic) crises occur in patients with myasthenia gravis due to improper use and/or an initially narrow range of therapeutic doses of AChE inhibitors, as well as against the background of conditions causing general or muscle weakness of various origins (intercurrent infections, somatic, hormonal disorders, taking medications, affecting the contractile function of voluntary muscles, etc.).

2.3 Laboratory diagnostics

• Determination of anticholinesterase antibodies is recommended.

Comments: Antibodies to AChR are detected in children in the range of 60-80%. In prepubertal age, the test is positive in approximately 50% of children. Antibody titers decrease in successfully treated patients. Of those seronegative for antibodies to AChR, about 40-50% are seronegative for antibodies to MySK. The higher incidence of these antibodies in children is not clearly established, but they may be present at the onset of the disease in early childhood.

2.4 Instrumental diagnostics

• Iterative nerve stimulation (INS) is recommended to detect electrical neuromuscular blockade.

Comments: This test is stressful, especially in young children, and should therefore be performed gently. Technical difficulties in young children are also a problem, and therefore, before declaring a test positive, one must be completely sure that the decrease in amplitude is of a myasthenic type. Total muscle action potentials are recorded from surface electrodes, preferably over weak muscles; nerve stimulation frequency 3Hz and 5Hz. A decrease in amplitude by more than 10% between the third and fifth potentials is considered a positive result. Single-fiber EMG, which makes it possible to detect increased “tremor” during contraction of pairs of fibers, is more sensitive than classical ISN, but is a difficult method to perform in children. Normal ISN does not exclude the diagnosis of JMG.

• It is recommended that in diagnostically difficult cases, a morphological examination of the muscle biopsy is carried out (light, electron microscopy, histochemical, immunohistochemical, immunofluorescent and other types of visual examination of the neuromuscular junction and surrounding tissues).

Comments: The main qualitative and quantitative changes in myasthenia gravis are found in the postsynaptic membrane, which contains AChRs, and in the stage of a full-blown clinical picture, the number of AChRs decreases to 10-30% of normal values, and their density decreases.

2.5 Other diagnostics

• The use of anticholinesterase drugs is recommended - a test with AChE inhibitors: neostigmine methyl sulfate (ATC code: N07AA01), pyridostigmine hydrochloride (ATC code: N07AA02). After one of these drugs is administered, the effect is observed in one or more weakened muscles. The most common test is neostigmine methyl sulfate. The dose is selected individually at the rate of 0.125 mg/kg body weight (approximately: 1.5 ml of a 0.05% solution for a body weight of up to 70 kg and 2 ml for a body weight of more than 70 kg or for severe generalized weakness of the muscles of the limbs without taking into account body weight). Any parenteral route of administration of the drug can be chosen, but subcutaneous injection is usually done. The effect of the drug is assessed after 30-40 minutes .

Comments:A positive complete test is considered when muscle strength is restored to 5 points with compensation for bulbar and oculomotor disorders, a positive incomplete test is considered when strength increases by 1-2 points, but without its complete restoration and (or) preservation of a reduced bulbar or oculomotor defect. Partial compensation consists of the selective action of AChE inhibitors on individual muscle groups, as a rule, with an increase in the strength of voluntary muscles by 1 point. A questionable proserine test is identified when some positive dynamics are noted in relation to individual symptoms (a decrease in ptosis by 1-2 mm, a slight increase in the range of movements of the eyeballs, a slightly clearer voice, an impression of a slight increase in the strength of the muscles of the limbs, etc.

• It is recommended to administer intramuscular or subcutaneous neostigmine methyl sulfate if a transient neonatal form (neonatal myasthenia) is suspected.

Comments: Clinical symptoms allow a correct diagnosis to be made if the mother is known to have myasthenia gravis, but the mother's disease may be undiagnosed or asymptomatic. The diagnosis is confirmed by intramuscular or subcutaneous administration of Neostigmine methyl sulfate (ATC code: N07AA01); ISN can also be performed to confirm the diagnosis, but its implementation at this age is technically difficult and painful. For diagnosis and then for treatment, it is preferable to use Neostigmine methyl sulfate (ATC code: N07AA01, Proserin), especially before feeding, since its effect lasts longer, which allows more time for examination (for example, a single dose of 0.1 mg before feeding , and additional doses as needed).

If the diagnosis of myasthenia gravis is in doubt, dynamic observation, a trial course of AChE inhibitors (pyridostigmine hydrochloride in combination with potassium preparations - only strictly avoiding cholinergic reactions), repeated clinical and electromyographic (EMG) examination are required.

The anticholinesterase test and SRI do not have high sensitivity and specificity, while the presence of antibodies to AChR is specific for myasthenia gravis.

2.6 Differential diagnosis.

The diagnosis of myasthenia gravis is made on the basis of a combination of clinical data and the results of instrumental examinations. The main difference between myasthenia gravis and other forms of pathology is the dynamics of symptoms and a positive reaction to the administration of anticholinesterase drugs.

The following diseases must be excluded:

- endocrine ophthalmopathy;

- oculopharyngeal muscular dystrophy;

- multiple sclerosis;

- Fisher syndrome;

- botulism;

- Tolosa-Hunt syndrome;

- mitochondrial cytopathies;

- congenital myasthenic syndromes, etc.

Bulbar manifestations of myasthenia gravis should be differentiated from vascular and tumor lesions of the brain, which are characterized by pronounced general cerebral symptoms, as well as the lack of dynamic disorders and response to the administration of anticholinesterase drugs.

Sometimes significant difficulties arise in the differential diagnosis of myasthenia gravis and amyotrophic lateral sclerosis (ALS), in which in some cases not only clinical symptoms of myasthenia gravis are possible, but also disorders of neuromuscular transmission and the response to the administration of anticholinesterase drugs. In such cases, a correct diagnosis can be made only after an EMG has been performed, revealing signs of denervation and reinnervation, as well as the presence of a large number of fasciculatory potentials characteristic of ALS. Respiratory disorders and crises in myasthenia gravis should be differentiated from Guillain-Barré syndrome (GBS), which is characterized by areflexia, disturbances in the composition of the cerebrospinal fluid, the absence of disorders of neuromuscular transmission and reactions to the administration of anticholinesterase drugs.

Weakness of the muscles of the trunk and limbs in patients with myasthenia gravis is differentiated with various forms of congenital and acquired myopathies.

The myopathic process, as a rule, is characterized by a distribution of movement disorders different from myasthenia: the absence (with rare exceptions) of signs of damage to the extraocular and bulbar muscles, respiratory disorders; often accompanied by a decrease or absence of tendon reflexes and varying degrees of muscle atrophy.

Clinical symptoms resembling myasthenia gravis are also possible with other forms of neuromuscular transmission disorders, such as Lambert-Eaton syndrome and botulism. And if extraocular, bulbar and respiratory disorders are not typical for Lambert-Eaton syndrome, then they form the main clinical core of botulism. Weakness and fatigue of the muscles of the trunk and limbs, characteristic of Lambert-Eaton syndrome, are detected relatively rarely during botulism. Both forms are characterized by hypo- or areflexia.

The effect of the administration of anticholinesterase drugs in Lambert-Eaton syndrome is minimal, and absent in botulism. Disorders of neuromuscular transmission are characterized by a decrease in the initial amplitude of the M-response and its significant increase during high-frequency stimulation (increment) or after maximum voluntary effort.

3. Treatment

3.1 Conservative treatment

• The use of cholinesterase blockers is recommended.

Comments: These drugs increase the half-life of acetylcholine (ACh) released into the synaptic cleft by inhibiting its hydrolysis by acetylcholinesterase, thereby increasing the likelihood that ACh molecules will reach receptors that are reduced in number.

• Pyridostigmine bromide w, vk (code ATX:N07AA02) at a dose of up to 7 mg/kg/day is prescribed in 3-5 doses.
• Neostigmine methyl sulfate w, vk (ATC code: N07AA01) the initial dose is 0.2-0.5 mg/kg every four hours in children under 5 years of age and 0.25 mg/kg in older children, the maximum single dose is 15 mg.

• The use of corticosteroids is recommended.

Comments:GCS induce remission in most children with JMG. Prednisolone w, vk (ATC code: H02AB06) is prescribed at a dose of 1-2 mg/kg/day until a stable effect is achieved, after which the drug is gradually withdrawn.

• The use of other types of long-term immunotherapy is recommended.

Comments:

• Azathioprine w,vk (code ATX:L04AX01) can be used in combination with steroids or alone. The initial dose is 50 mg/day and up to 100–200 mg/day along with a maintenance dose of Prednisolone.
• Cyclosporine (ATC code: L04AD01) can be prescribed if Azathioprine is intolerant.
• Cyclophosphamide g, vk (ATC code: L01AA01) is used for very severe disease.
• Pulse therapy with high doses of Methylprednisolone w, vk (H02AB04) is used in children with refractory disease.

• The use of plasma replacement is recommended.

Comments:Plasmapheresis is used to treat myasthenic crises, as well as for pre- and post-operative support. Intravenous administration of immunoglobulins of class G is carried out - human immunoglobulin normal g, vk (ATC code: J06BA02, Human immunoglobulin normal) The effect is observed after 3-4 days and lasts up to 3 months.

3.2 Surgical treatment

• The use of thymectomy is recommended.

Comments: used as the main method of long-term treatment, especially in children with a high risk of developing complications from treatment with ChE blockers or corticosteroids, or other types of immunotherapy.

Indications for surgical treatment are:

a) malignant forms;

b) progressive form;

c) myasthenic condition, depending on the severity of the defect.

For local forms, surgical treatment is approached selectively.

Contraindications to thymectomy:

• severe decompensated somatic diseases;

Before surgical treatment, preoperative preparation is required:

• restorative therapy;
• carrying out therapeutic plasmapheresis;
• if necessary, a course of glucocorticosteroid therapy.

4. Rehabilitation

Not required

5. Prevention and clinical observation

5.1 Prevention

Prevention has not been developed.

5.2 Patient management

Management of patients with myasthenia gravis in an outpatient setting should include:

• ECG for all children once every 3 months.
• ?Ultrasound abdominal cavity, heart, kidneys - once every 6 months.
• X-ray examination of the chest, joints, if necessary, the spine, sacroiliac joints - once every 6 months.
• ?esophagogastroduodenoscopy with biopsy for Helicobacter pylori and morphological diagnosis - once every 6 months to exclude erosive, ulcerative processes and gastropathy.
• ?in case of exacerbation - ultrasound internal organs and chest X-ray, ECG and other necessary instrumental examination methods (CT, MRI) according to indications:
• patients with myasthenia gravis are given a Mantoux test; examination for tuberculosis is carried out under the supervision of a phthisiatrician
• if positive tuberculin tests are detected (papule > 5 mm), referral for consultation to a phthisiatrician to decide on conducting a Diaskin test or tuberculin tests with dilution and specific therapy

Management of a patient receiving immunosuppressive therapy

• examination by a neurologist – once a month;
• clinical blood test (hemoglobin concentration, number of red blood cells, platelets, leukocytes, leukocyte formula, ESR) - once every 2 weeks;
• ?as the number decreases leukocytes, erythrocytes, platelets are below normal - stop immunosuppressants for 5–7 days. After a control blood test and if the parameters are normalized, resume taking the drug;
• urea, creatinine, bilirubin, potassium, sodium, ionized calcium, transaminases, alkaline phosphatase) - once every 2 weeks:
• if the level of urea, creatinine, transaminases, bilirubin increases above normal - stop immunosuppressants for 5–7 days. Resume taking the drug after restoration of biochemical parameters;
• analysis of immunological parameters (concentration of Ig A, M, G; CRP, RF, ANF) - once every 3 months.

Management of a patient with myasthenia gravis receiving anticholinesterase drugs

• ?examination by a neurologist once a month;
• ? clinical blood test (hemoglobin concentration, number of red blood cells, platelets, leukocytes, leukocyte formula, ESR) - once every 2 weeks;
• ?analysis of biochemical parameters (total protein, protein fractions, concentration urea, creatinine, bilirubin, potassium, sodium, ionized calcium, transaminases, alkaline phosphatase) - once every 2 weeks;
• ? analysis of immunological parameters (concentration of Ig A, M, G; CRP, RF, ANF) - once every 3 months;
• planned hospitalization 2 times a year for a full examination and, if necessary, correction of therapy.

Patients with myasthenia gravis are advised to obtain the “disabled child” status. During periods of exacerbation of the disease, it is necessary to provide home education. In the stage of remission of the disease, exercise therapy sessions with a specialist familiar with the features of the pathology are recommended. When visiting school? Physical education classes in the general group are not indicated. Are preventive vaccinations and administration contraindicated for patients with myasthenia gravis? globulin.

Patients diagnosed with myasthenia gravis should be under constant medical supervision of a pediatrician and neurologist. Children with this pathology are recommended for a comprehensive examination in a specialized 24-hour/day hospital; the average duration of hospitalization is 21 days. It is advisable to conduct courses of rehabilitation therapy for a period of at least 21-28 days 2-3 times a year under the supervision of a neurologist, physiotherapist and exercise therapy specialist.

6. Additional information affecting the course and outcome of the disease

6.1 Outcomes and prognosis

The most severe course of myasthenia gravis is observed in children with multiple stigmas of dysembryogenesis (musculoskeletal dysplasia, developmental abnormalities of the central nervous system), neuroendocrine disorders (diencephalic-temporal paroxysmal conditions, delayed growth and puberty against the background of hypopituitary syndrome, acquired hirsutism and others), immaturity lymphoid system of the nasopharynx (adenoids, tonsillitis, pharyngitis), broncho-obstructive syndrome and other concomitant pathologies. In boys with the onset of the disease in the prepubertal period and regression of myasthenia gravis symptoms by the end of puberty, as a rule, persistent remissions are observed.

Choosing the right treatment tactics allows you to achieve a positive effect (stable complete or partial remission with or without medication) in 80% of patients with myasthenia gravis. However, to date there are no methods for predicting the course of the disease and specific pathogenetic methods for treating myasthenia gravis.

Criteria for assessing the quality of medical care

Table 1 - Organizational and technical conditions for the provision of medical care.

Table 2 - Criteria for the quality of medical care

	Criterion	Level of evidence
	Determination of anticholinesterase antibodies, test with AChE inhibitors was performed
	Iterative nerve stimulation was performed
	Cholinesterase blockers were used (in the absence of medical contraindications)
	Immunosuppressive therapy with glucocorticosteroids was carried out (in the absence of medical contraindications)

References

1. Autoimmune diseases of neuromuscular transmission. In the book: A short reference book for a neurologist. – M.: “ABV-press”, 2015. – P. 129-139.
2. Guzeva V.I., Chukhlovina M.L. Clinical guidelines for the diagnosis and treatment of myasthenia gravis in children. In the book: Child neurology. Issue 1: clinical recommendations / ed. V.I. Guzevoy. – M.: LLC “MK”, 2014. – P. 101-127.
3. Sanadze A.G. Myasthenia. In the book: Autoimmune diseases in neurology. Under. ed. Zavalishina I.A., Piradova M.A., Boyko A.N., Nikitina S.S., Spirina N.N., Peresedova A.V. Clinical guidelines. – T.2. – M.: ROOI “Human Health”, 2014. – P. 101-128.
4. Aicardi J. Diseases of the nervous system in children. - T.2. – M.: Binom, 2013. – P. 940-949.
5. Sanadze A.G. Myasthenia and myasthenic syndromes. M.: Litterra, 2012. – 256 p.
6. Suponeva N.A., Piradov M.A. Myasthenia gravis. In the book: Intravenous immunotherapy in neurology. M: Hotline-Telecom, 2013. – P. 165-191.
7. Kaminski H.J. Myasthenia gravis. In book: Neuromuscular disorders in clinical practice (Eds. Katirji B., Kaminski H.J., Ruff R.L.). – New York: Springer, 2014. – P. 1075-1088.
8. Parr J., Jayawant S., Buckley C., Vincent A. Childhood autoimmune myasthenia. In book: Inflammatory and autoimmune disorders of the nervous system in children (Eds. Dale R.C., Vincent A.). London: Mac Keith Press, 2010. – P. 388-405.

Appendix A1. Composition of the working group

Baranov A.A., acad. RAS, professor, doctor of medical sciences, Chairman of the Executive Committee of the Union of Pediatricians of Russia.

Namazova-Baranova L.S., acad. RAS, Professor, Doctor of Medical Sciences, Deputy Chairman of the Executive Committee of the Union of Pediatricians of Russia.

Kurenkov A.L.,

Kuzenkova L.M., Professor, Doctor of Medical Sciences, member of the Union of Pediatricians of Russia

Goltsova N.V.,

Mamedyarov A.M., Ph.D., member of the Union of Pediatricians of Russia

Bursagova B.I., Candidate of Medical Sciences, member of the Union of Pediatricians of Russia

Vishneva E.A., Candidate of Medical Sciences, member of the Union of Pediatricians of Russia

1. Pediatricians, neurologists;
2. Orthopedic doctors;
3. Exercise therapy doctors, physiotherapists,
4. General practitioners (family doctors);
5. Students of medical universities;
6. Students in residency and internship.

Methods used for collecting/selecting evidence: searching electronic databases.

Description of methods used to assess the quality and strength of evidence: the evidence base for recommendations is publications included in the Cochrane Library, EMBASE, MEDLINE and PubMed databases. Search depth - 5 years.

Methods used to assess the quality and strength of evidence:

• expert consensus;
• assessment of significance in accordance with the rating scheme.

Methods used to analyze evidence:

• reviews of published meta-analyses;
• systematic reviews with evidence tables.

Description of the methods used to analyze the evidence

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The outcome of the study influences the level of evidence assigned to the publication, which in turn influences the strength of the recommendations.

To minimize potential bias, each study was assessed independently. Any differences in ratings were discussed by the entire writing group. If it was impossible to reach consensus, an independent expert was involved.

Evidence tables: filled out by the authors of clinical guidelines.

Methods used to formulate recommendations: expert consensus.

Economic analysis

No cost analysis was performed and pharmacoeconomics publications were not reviewed.

• External expert assessment.
• Internal expert assessment.

These draft recommendations were peer-reviewed by independent experts who were primarily asked to comment on the extent to which the interpretation of the evidence underlying the recommendations was understandable.

Comments were received from primary care physicians regarding the clarity of these recommendations, as well as their assessment of the importance of the proposed recommendations as a tool for daily practice.

All comments received from experts were carefully systematized and discussed by members of the working group (authors of the recommendations). Each point was discussed separately.

Consultation and expert assessment

Working group

For final revision and quality control, the recommendations were re-analyzed by members of the working group, who concluded that all comments and comments from experts were taken into account, and the risk of systematic errors in the development of recommendations was minimized.

Table P1 - Scheme for assessing the level of recommendations

	Risk-benefit ratio	Methodological quality of available evidence
		Reliable consistent evidence based on well-performed RCTs or compelling evidence presented in some other form.
	The benefits clearly outweigh the risks and costs, or vice versa	Evidence based on the results of RCTs performed with some limitations (inconsistent results, methodological errors, indirect or random, etc.) or other compelling reasons. Further studies (if conducted) are likely to influence and may change our confidence in the benefit-risk estimate.
	The benefits are likely to outweigh the potential risks and costs, or vice versa	Evidence based on observational studies, unsystematic clinical experience, results of RCTs performed with significant shortcomings. Any estimate of effect is considered uncertain.
	The benefits are comparable to the possible risks and costs	Reliable evidence based on well-performed RCTs or supported by other compelling data. Further research is unlikely to change our confidence in the benefit-risk assessment.	The choice of the best strategy will depend on the clinical situation(s), patient, or social preferences.
	The benefits are comparable to the risks and complications, but there is uncertainty in this assessment.	Evidence based on the results of RCTs performed with significant limitations (inconsistent results, methodological flaws, indirect or random), or strong evidence presented in some other form. Further studies (if conducted) are likely to influence and may change our confidence in the benefit-risk estimate.	An alternative strategy may be a better choice for some patients in certain situations.
	Ambiguity in assessing the balance of benefits, risks and complications; the benefits may be weighed against the possible risks and complications.	Evidence based on observational studies, anecdotal clinical experience, or RCTs with significant limitations. Any estimate of effect is considered uncertain.

*In the table, the numerical value corresponds to the strength of recommendations, the letter value corresponds to the level of evidence

These clinical recommendations will be updated at least once every three years. The decision to update will be made on the basis of proposals submitted by medical professional non-profit organizations, taking into account the results of a comprehensive assessment of drugs, medical devices, as well as the results of clinical testing.

Correction of AChE therapy is indicated

Appendix B: Patient Information

Myasthenia gravis is a severe autoimmune neuromuscular disease with a progressive course, clinically manifested by pathological muscle fatigue leading to paresis and paralysis. Immunological disorders in myasthenia gravis are genetically determined.

Myasthenia gravis affects both males and females. The onset of the disease can occur at any age: from the first days of life to (neonatal myasthenia) to old age.

The disease is progressive in nature and quickly leads to disability and social maladjustment.

Appendix D

Appendix G1. Congenital myasthenic syndromes

Disorder	Neurophysiology	Clinical picture	Genetics
Presynaptic
Congenital myasthenic syndromes with episodic apnea	Decremental response	Occasional apnea or cessation of breathing at any time after birth, often caused by infection. Ophthalmoplegia is uncommon. Cholinesterase blockers are effective and the condition improves with age.	Mutation of the gene encoding choline acetyltransferase
Other syndromes with decreased acetylcholine release		In some patients it resembles Lambert-Eaton myasthenic syndrome, in others it manifests as mild ataxia or cerebellar nystagmus.
Synaptic
Membrane acetylcholinesterase deficiency	Repetitive and decremental SPDM with a single nerve stimulation	Often severe with ophthalmoplegia and weakness, especially of the axial muscles. Slow pupillary reaction to light. The use of cholinesterase blockers is ineffective or causes worsening of the condition.	Mutation of the COLQ gene, encoding the collagen “tail” of acetylcholinesterase
Postsynaptic	Receptor insufficiency, kinetic abnormalities, or disruption of receptor grouping.
AChR deficiency	Single answer	Severity ranges from light to heavy. Early debut. Ptosis, ophthalmoplegia, oropharyngeal symptoms, limb weakness. May improve with treatment with ACChE blockers and 3,4-DAP. Moderate disability.	Mutations of AChR subunit genes
Anomalies in AChR kinetics
A. Slow channel syndrome (SCS)	Repeated SPDM with single nerve stimulation	Age of onset and severity are variable. Selective weakness of the muscles of the neck, scapula and finger extensors. Mild ophthalmoplegia. May worsen with the use of ACChE blockers. Quinidine and fluoxetine are used, but the risk of severe side effects is high.	Usually autosomal dominant. Autosomal recessive inheritance has been described.
B. Fast channel syndrome (FCS)		Variable phenotype, from mild to severe. ACChE blockers alone or with 3,4-DAP are effective, but the death of two children was described after starting treatment, although the cause of death due to 3,4-DAP has not been proven.	Various mutations in AChR subunit genes
Abnormalities of AChR aggregation: membrane rapsin deficiency
A. Rapsin-RD (early debut)	Often normal ISN	Mild arthrogryposis, hypotension, oropharyngeal dysfunction, episodic apnea or respiratory arrest from birth, some - facial dysmorphism, ophthalmoplegia - rarely. AChR blockers mono or with 3,4-DAP are effective
V. Rapsin PD (late debut)		Debut in adolescence or adulthood. Misdiagnosis of seronegative MG. ACChE blockers are effective.
Muscle receptor tyrosine kinase	Decremental response	Debut in the neonatal period. Ptosis and respiratory distress.	Mutations in the gene encoding muscle-specific receptor tyrosine kinase
SCN4A (Nav.1.4) sodium channel	Decremental response	Ptosis, weakness, recurrent respiratory and bulbar paralysis	Mutations in the gene encoding voltage-dependent sodium channels SCN4A (Nav.1.4)

AChR acetylcholine receptor; AChE blocker – acetylcholinesterase blocker; SPDM – total muscle action potential; 3,4-DAP – 3,4-diaminopyridine; ISN – iterative nerve stimulation; MG – myasthenia gravis.

Appendix G2. Distinctive symptoms of myasthenic and cholinergic crises

Myasthenic crisis	Cholinergic crisis
M-cholinergic (autonomic) symptoms
Dry mucous membranes Thick saliva Tachycardia Increased blood pressure	Lacrimation, bronchorrhea, rhinorrhea Liquid saliva Bradycardia Decreased blood pressure Nausea, vomiting, intestinal colic, loose stools, polyuria
N-cholinergic symptoms
Positive reaction to the administration of anticholinesterase drugs	Deterioration of the condition due to the administration of anticholinesterase drugs Fascicular muscle twitching Crumpy, muscle tremors Epileptiform seizures

Appendix G3. Explanation of notes.

… and - a medicinal product included in the List of vital and essential medicinal products for medical use for 2016 (Order of the Government of the Russian Federation dated December 26, 2015 N 2724-r)

... VK – a medicinal product included in the List of medicinal products for medical use, including medicinal products for medical use prescribed by decision of medical commissions of medical organizations (Order of the Government of the Russian Federation dated December 26, 2015 N 2724-r)

Myasthenia gravis is the most common autoimmune disease characterized by damage to the neuromuscular synapses due to the production of autoantibodies to acetylcholine receptors or to specific enzymes - muscle-specific tyrosine kinase.

As a result, pathological fatigue and weakness of skeletal muscles develop, mutations in proteins of neuromuscular junctions can lead to the development of congenital myasthenic syndromes.

What is it?

Myasthenia gravis is a fairly rare autoimmune disease characterized by muscle weakness and lethargy. With myasthenia gravis, there is a disruption in the communication between nerve and muscle tissues.

The official scientific name of this disease is myasthenia gravis pseudoparalitica, which is translated into Russian as asthenic bulbar palsy. In Russian medical terminology, the concept of “myasthenia gravis” is widely used.

Causes of myasthenia gravis

To date, experts do not have clear information about what exactly provokes the symptoms of myasthenia gravis in a person. Myasthenia gravis is an autoimmune disease, because multiple autoantibodies are found in the serum of patients. Doctors record a certain number of familial cases of myasthenia gravis, but there is no evidence of the influence of hereditary factors on the manifestation of the disease.

Quite often, myasthenia gravis manifests itself in parallel with hyperplasia or a tumor of the thymus gland. Also, myasthenic syndrome can occur in patients who complain of organic diseases of the nervous system, polydermatomyositis, and cancer.

More often, females suffer from myasthenia gravis. As a rule, the disease manifests itself in people aged 20–30 years. In general, the disease is diagnosed in patients aged 3 to 80 years. In recent years, experts have shown significant interest in this disease due to the high incidence of myasthenia gravis in children and young people, which leads to subsequent disability. This disease was first described more than a century ago.

Pathogenesis

Autoimmune processes play a role in the development of myasthenia gravis; antibodies were found in muscle tissue and the thymus gland. The muscles of the eyelids are often affected, resulting in ptosis that varies in severity throughout the day; chewing muscles are affected, swallowing is impaired, and gait changes. It is harmful for patients to be nervous, as this causes chest pain and shortness of breath.

The provoking factor may be stress, suffered from ARVI, dysfunction of the body's immune system leads to the formation of antibodies against the body's own cells - against acetylcholine receptors of the postsynaptic membrane of neuromuscular junctions (synapses). Autoimmune myasthenia gravis is not inherited.

Most often, the disease manifests itself during adolescence in girls (11-13 years old); it is less common in boys at the same age. The disease is increasingly being detected in preschool children (5-7 years old).

Classification

This disease develops differently in everyone. Most often, myasthenia gravis begins with weakness of the eye and facial muscles, then this disorder spreads to the muscles of the neck and torso. But some people have only some signs of the disease. Accordingly, there are several types of myasthenia gravis.

1. The ocular form is characterized by damage to the cranial nerves. The first sign of this is drooping of the upper eyelid, most often on one side first. The patient complains of double vision and difficulty moving the eyeballs.
2. The bulbar form of myasthenia gravis is a lesion of the masticatory and swallowing muscles. In addition to the disruption of these functions, the patient’s speech changes, the voice becomes quiet, nasal, and there are difficulties in pronouncing certain sounds, for example, “r” or “b”.
3. But most often there is a generalized form of the disease, in which the eye muscles are first affected, then the process spreads to the neck, upper and lower extremities. The hips and arm muscles are especially often affected; it is difficult for the patient to climb stairs or hold objects. The danger of this form of the disease is that weakness spreads to the respiratory muscles.

Symptoms

Unfortunately, most often myasthenia gravis is diagnosed in cases where the disease continues for several years in a row and becomes advanced. For this reason, any unexplained fatigue, muscle flaccidity, or weakness that increases sharply with repeated movements should be regarded as a possible symptom of myasthenia gravis until this diagnosis is completely refuted.

Early symptoms include:

• swallowing disorder
• difficulty chewing solid food to the point of refusing to eat,
• when talking - “fading of voice”,
• fatigue when combing, climbing stairs, normal walking,
• the appearance of a shuffling gait,
• drooping eyelids.

The most often affected are the oculomotor, facial, and masticatory muscles, as well as the muscles of the larynx and pharynx. The following tests help identify latent myasthenia gravis:

• If a patient is asked to quickly open and close his mouth within 30 seconds, a healthy person will make about 100 movements, and a person suffering from myasthenia gravis will make less.
• Lie on your back, raise your head and hold it in this position for 1 minute, while looking at your stomach.
• Extend your arms and stand there for 3 minutes.
• Do 15–20 deep squats.
• Quickly clench and unclench your hands - this often causes drooping eyelids in a patient with myasthenia gravis.

The local form of myasthenia gravis is characterized by the manifestation of muscle weakness of a certain group of muscles, and in the generalized form, the muscles of the trunk or limbs are involved in the process.

Myasthenic crisis

As clinical practice shows, myasthenia gravis is a progressive disease, which means that under the influence of certain paralysis factors (external environment or endogenous causes), the degree and severity of symptomatic manifestations of the disease can increase. And even patients with mild myasthenia gravis can experience a myasthenic crisis.

The cause of this condition may be:

• injuries;
• stressful conditions:
• any acute infections;
• taking medications with neuroleptic or tranquilizing effects;
• surgical interventions in the body, etc.

Symptoms are manifested by the first appearance of double vision. Then the patient feels a suddenly increasing attack of muscle weakness, the motor activity of the muscles of the larynx decreases, which leads to disruption of the processes:

• voice formation;
• breathing and swallowing;
• salivation increases and the pulse quickens;
• The pupils may dilate, tachycardia may occur, and complete paralysis may occur without loss of sensitivity.

The development of acute insufficiency of oxygen supply to the brain can lead to a direct threat to life, so resuscitation measures are urgently necessary.

Diagnostics

In order to make a correct diagnosis, the patient is prescribed a comprehensive study, since the clinical picture of myasthenia gravis may be similar to other diseases. The main diagnostic methods are:

1. Extensive biochemical blood tests to detect antibodies;
2. Electromyography is a study during which you can evaluate the potential of muscle fibers when they are excited;
3. Genetic screening, which is carried out to identify the congenital form of myasthenia;
4. Electroneurography is a study that allows you to evaluate the speed of transmission of nerve impulses to muscle fibers;
5. MRI – with the help of this study, you can notice even the slightest signs of thymic hyperplasia;
6. Test for muscle fatigue - the patient is asked to quickly open and close his mouth several times, wave his arms and legs, clench and unclench his hands, and squat. The main syndrome of myasthenia gravis is the appearance of increasing muscle weakness with repetition of these movements.
7. Proserine test - the patient is injected subcutaneously with proserine, after which they wait for up to half an hour, and then evaluate the result. A patient with myasthenia gravis feels a significant improvement in his condition, and after a few hours the clinical symptoms resume with the same intensity.

How to treat myasthenia gravis?

In severe cases of myasthenia gravis, removal of the thymus gland during surgery is indicated. The most effective medications successfully used to relieve symptoms of the disease include prozerin and kalinin. Along with them, medications that enhance immunity and a number of other medications that improve the patient’s well-being are used. It is important to remember that the earlier treatment is started, the more effective it will be.

At the first stage of the disease, anticholinesterase drugs, cytostatics, glucocorticoids and immunoglobulins are used as symptomatic therapy. If the cause of myasthenia gravis is a tumor, then surgery is performed to remove it. In cases where the symptoms of myasthenia gravis rapidly progress, extracorporeal hemocorrection is indicated to clear the blood of antibodies. Already after the first procedure, the patient notices an improvement in his condition; for a more lasting effect, treatment is carried out for several days.

New, effective methods of treatment include cryophoresis - purification of the blood from harmful substances under the influence of low temperatures. The procedure is carried out in a course (5–7 days). The advantages of cryophoresis over plasmaphoresis are obvious: in the plasma that is returned to the patient after purification, all useful substances are preserved unchanged, which helps to avoid allergic reactions and viral infection.

Also new methods of hemocorrection used in the treatment of myasthenia gravis include cascade plasma filtration, in which purified blood, after passing through nanofilters, returns to the patient. After the first minutes of the procedure, the patient notices an improvement in well-being; the full course of treatment for myasthenia gravis requires five to seven days.

Modern methods of treating myasthenia gravis also include extracorporeal immunopharmacotherapy. As part of the procedure, lymphocytes are isolated from the patient's blood, which are treated with medications and sent back into the patient's bloodstream. This procedure is considered the most effective in the treatment of myasthenia gravis. It allows you to reduce the activity of the immune system by reducing the production of lymphocytes and antibodies. This technique gives stable remission for a year.

Prevention of myasthenia gravis and its complications

It is impossible to prevent the disease, but you can do everything possible to live a full life with such a diagnosis.

1. Firstly, doctor's control. Such patients are managed by neurologists. In addition to the prescribed treatment regimen and systematic visits to a neurologist, it is necessary to monitor the general condition (blood sugar, blood pressure, etc.) in order to prevent the development of other diseases during the treatment of myasthenia gravis.
2. Secondly, you should avoid excessive stress - physical and emotional. Stress, hard physical work, and overly active sports worsen the condition of patients. Moderate exercise and walking are even beneficial.
3. Thirdly, you should avoid exposure to the sun.
4. Fourthly, it is necessary to know the contraindications for patients with myasthenia gravis and strictly observe them.
5. Fifthly, strictly follow the treatment regimen prescribed by the doctor, do not skip medications and do not take more medications than prescribed by the attending physician.

The doctor is obliged to issue a list of medications contraindicated for such a patient. It includes magnesium preparations, muscle relaxants, tranquilizers, some antibiotics, diuretics with the exception of veroshpiron, which, on the contrary, is indicated.

You should not get carried away with immunomodulatory drugs or any sedatives, even those that seem safe (for example, valerian or peony tincture).

Forecast

Previously, myasthenia gravis was a serious disease with a high mortality rate of 30-40%. However, with modern methods of diagnosis and treatment, mortality has become minimal - less than 1%; about 80%, with proper treatment, achieve complete recovery or remission. The disease is chronic, but requires careful monitoring and treatment.

  When collecting anamnesis and complaints, attention is paid to the variability of symptoms during the day, their connection with the load, the presence of partial or complete remissions, reversibility of symptoms while taking AChE inhibitors (for the duration of their action) and against the background of adequate immunosuppressive therapy.

2.2 Physical examination.

  A clinical examination should include a study of the general neurological status, as well as checking the strength of the voluntary muscles of the face, neck, trunk and limbs before and after exercise (strength assessment in points, where 0 is no strength, 5 is the strength of a given muscle group in a healthy person). One of the most important clinical tests for diagnosing myasthenia gravis is the presence of pathological muscle fatigue syndrome: an increase in symptoms after exercise. For example, an increase in ptosis, oculomotor disturbances during gaze fixation, after squinting; decrease in strength in certain muscle groups after repeated active movements in the limb under study, squats or walking; the appearance or increase of speech disorders when counting, reading aloud. In this case, no symptoms of organic damage to the nervous and neuromuscular system are detected (in the absence of concomitant diseases): there are no disorders in the reflex and coordination spheres, sensitivity is preserved, in typical cases there are no muscle atrophies, preserved muscle tone.
  Juvenile autoimmune myasthenia gravis (JMG).
  Symptoms of the disease can develop at any age over one year, but most often appear in girls during adolescence. The onset of the disease may be gradual or sudden.
  The clinical picture is characterized by:
  damage to the extraocular muscles with diplopia, ophthalmoplegia and ptosis (can be symmetrical, asymmetrical or unilateral).
  weakness of the facial muscles (especially the orbicularis oculi muscle).
  weakness of the proximal limbs.
  damage to the respiratory and oropharyngeal muscles.
  deep tendon reflexes are preserved.
  When examining children with developed respiratory failure in the absence of pulmonary pathology, it is necessary to take into account the possibility of JMG, even if there are no other symptoms of this disease.
  Initially, muscle strength may be normal or nearly normal, and muscle strength should therefore be assessed before and after exercise.
  The incidence of cases in which involvement is limited to the extraocular muscles only (ocular myasthenia gravis) varies widely among different publications, but is probably 20–50%, and up to 80% in young children in China. MuSK-MG is more common in women; the clinical picture is dominated by weakness of the oculomotor and cranial muscles, and frequent respiratory crises are noted. The differences between MuSK-MG and AChR-MG remain to be elucidated.
  Transient neonatal form (neonatal myasthenia).
  Clinical manifestations include:
  general muscle hypotonia.
  weak cry.
  difficulty breathing and sucking.
  Possible development of ptosis.
  amymia, oculomotor disorders.
  swallowing disorders, decreased deep reflexes.
  Congenital myasthenic syndromes are presented in more detail in Appendix D1.
  Transient myasthenic syndrome, which manifests itself in such children in the first days of life and lasts for 1-1.5 months. , is caused by the transfer of antibodies to AChR from the mother through the placental barrier.
  concomitant diseases, and are a hallmark of the condition now called IUD with episodic apnea).
  Thus, the difference between all the symptoms of myasthenia gravis is their dynamism during the day, intensification after exercise, reversibility or a decrease in their severity after rest.
  Myasthenic crisis, in which, for various reasons, there is a sharp deterioration in the condition with disruption of vital functions. The molecular basis of myasthenic crisis is probably a sharp decrease in the number of functioning AChRs due to a massive attack by their autoantibodies. Often, myasthenic crisis is provoked by a bronchopulmonary infection, and in some cases, pneumonia develops against the background of the crisis, and then breathing problems can be of a mixed nature.
  Myasthenic crisis can be differentiated from other severe conditions accompanied by respiratory disorders by the presence of:
  bulbar syndrome.
  hypomia.
  ptosis,
  asymmetric external ophthalmoparesis.
  weakness and fatigue of the muscles of the limbs and neck (decreasing in response to the administration of AChE inhibitors).
  It is necessary to distinguish myasthenic crisis from cholinergic crisis (Appendix D2), which develops with an excessive dose of AChE inhibitors. Common symptoms of crises are severe weakness of voluntary muscles with respiratory failure and bulbar syndrome, psychomotor agitation and impaired consciousness (stupor, coma).
  Mixed (myasthenic + cholinergic) crises occur in patients with myasthenia gravis due to improper use and/or an initially narrow range of therapeutic doses of AChE inhibitors, as well as against the background of conditions causing general or muscle weakness of various origins (intercurrent infections, somatic, hormonal disorders, taking medications, affecting the contractile function of voluntary muscles, etc.;).

2.3 Laboratory diagnostics.

  Determination of anticholinesterase antibodies is recommended.
  Comments. Antibodies to AChR are detected in children in the range of 60-80%. In prepubertal age, the test is positive in approximately 50% of children. Antibody titers decrease in successfully treated patients. Of those seronegative for antibodies to AChR, about 40-50% are seronegative for antibodies to MySK. The higher incidence of these antibodies in children is not clearly established, but they may be present at the onset of the disease in early childhood.

2.4 Instrumental diagnostics.

  Iterative nerve stimulation (INS) is recommended to detect electrical neuromuscular blockade.
  (Strength of recommendation – 1; Strength of evidence – C).
  Comments. This test is stressful, especially in young children, and should therefore be performed gently. Technical difficulties in young children are also a problem, and therefore, before declaring a test positive, one must be completely sure that the decrease in amplitude is of a myasthenic type. Total muscle action potentials are recorded from surface electrodes, preferably over weak muscles; nerve stimulation frequency 3Hz and 5Hz. A decrease in amplitude by more than 10% between the third and fifth potentials is considered a positive result. Single-fiber EMG, which makes it possible to detect increased “tremor” during contraction of pairs of fibers, is more sensitive than classical ISN, but is a difficult method to perform in children. Normal ISN does not exclude the diagnosis of JMG.
  It is recommended that in diagnostically difficult cases, a morphological examination of the muscle biopsy is carried out (light, electron microscopy, histochemical, immunohistochemical, immunofluorescent and other types of visual examination of the neuromuscular junction and surrounding tissues).
  Comments. The main qualitative and quantitative changes in myasthenia gravis are found in the postsynaptic membrane, which contains AChRs, and in the stage of a full-blown clinical picture, the number of AChRs decreases to 10-30% of normal values, and their density decreases.

2.5 Other diagnostics.

  (Strength of recommendation – 1; Strength of evidence – C).
  The use of anticholinesterase drugs is recommended - a test with AChE inhibitors: neostigmine methyl sulfate (ATC code: N07AA01), pyridostigmine hydrochloride (ATC code: N07AA02). After one of these drugs is administered, the effect is observed in one or more weakened muscles. The most common test is neostigmine methyl sulfate. The dose is selected individually at the rate of 0.125 mg/kg body weight (approximately: 1.5 ml of a 0.05% solution for a body weight of up to 70 kg and 2 ml for a body weight of more than 70 kg or for severe generalized weakness of the muscles of the limbs without taking into account body weight). Any parenteral route of administration of the drug can be chosen, but subcutaneous injection is usually done. The effect of the drug is assessed after 30-40 minutes.
  Comments. A positive complete test is considered when muscle strength is restored to 5 points with compensation for bulbar and oculomotor disorders, a positive incomplete test is considered when strength increases by 1-2 points, but without its complete restoration and (or) preservation of a reduced bulbar or oculomotor defect. Partial compensation consists of the selective action of AChE inhibitors on individual muscle groups, as a rule, with an increase in the strength of voluntary muscles by 1 point. A questionable proserine test is identified when some positive dynamics are noted in relation to individual symptoms (a decrease in ptosis by 1-2 mm, a slight increase in the range of movements of the eyeballs, a slightly clearer voice, an impression of a slight increase in the strength of the muscles of the limbs.
  It is recommended to administer intramuscular or subcutaneous neostigmine methyl sulfate if a transient neonatal form (neonatal myasthenia) is suspected.