Complete cure for myasthenia gravis in a child. Myasthenia: symptoms. Treatment of Myasthenia in children

is an autoimmune disease that causes muscle weakness due to disruption of neuromuscular transmission. Most often, the work 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 lead to liquid entering the respiratory tract with 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 area (

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.

Myasthenia gravis is a disease of the neuromuscular system with a chronic, recurrent or progressive course, which belongs to the class of autoimmune processes with heterogeneous clinical manifestations. Pathological production of autoantibodies occurs as a result of dysfunction of the own immune system as a whole or its individual components, which leads to the destruction of organs and tissues of the body. Myasthenic syndrome is manifested by a whole range of clinical signs: drooping lower eyelid, nasal voice, dysphonia, dysphagia and problems with chewing. Disruption of neuromuscular transmission leads to weakness of the striated muscles of the eyes, face, and neck. Similar processes determine the symptoms characteristic of myasthenia gravis.

The term "myasthenia" translated from ancient Greek means "powerlessness or weakness of muscles." This is a classic autoimmune pathology, which is based on the self-destruction of body cells. The normal immune response changes its focus from foreign cells to its own.

The disease was first described in the 16th century. Currently, myasthenia gravis occurs in 6 people out of every 100 thousand. Women suffer from pathology much more often than men. The peak incidence occurs in people aged 20-40 years. Congenital forms of myasthenia gravis are also known. This disease is recorded not only in humans, but also in cats and dogs.

Muscle weakness can be an independent nosology - myasthenia gravis, or a manifestation of other psychosomatic diseases - myasthenic syndrome. But regardless of the main clinical form, the symptoms of the pathology are dynamic and labile. They intensify with physical activity or emotional stress, especially during the hot season. After rest, strength is quickly restored. Myasthenia gravis can last for a long time in a patient. At the same time, he himself does not even suspect that he has an illness. Sooner or later, a progressive disease will still make itself known.

Treatment of myasthenia gravis is aimed at restoring neuromuscular transmission. Since the disease is based on an autoimmune process, patients are prescribed hormonal drugs.

Etiology and pathogenesis

Currently, the etiopathogenetic factors of myasthenic syndrome have not been fully determined.

Possible causes of myasthenia gravis:

Hereditary predisposition - familial cases of the disease are known. The congenital form of myasthenia gravis is caused by a gene mutation that disrupts the normal functioning of myoneural synapses and interferes with the process of nerve-muscle interaction.
Tumor or benign hyperplasia of the thymus - thymomegaly.
Organic damage to the nervous system.
Systemic diseases - vasculitis, dermatomyositis, systemic lupus erythematosus.
Benign and malignant neoplasms of internal organs.
Hyperthyroidism - increased function of the thyroid gland.
Sleeping sickness.

With myasthenia gravis, the relationship between nerve and muscle tissues is disrupted. Provoking factors for the development of pathology are: stress, infections, immunodeficiency, trauma, long-term use of antipsychotics or tranquilizers, surgical interventions. They are the ones who trigger a complex autoimmune process in which the body forms antibodies to the body’s own cells - acetylcholine receptors.

Pathogenetic links of the syndrome:

production of autoantibodies to acetylcholine receptors;
damage to the neuromuscular synapse;
destruction of the postsynaptic membrane;
disruption of the synthesis, metabolism and release of acetylcholine - a special chemical substance that ensures the transmission of nerve impulses from the motor nerve to the muscle;
difficulty in neuromuscular conduction - insufficient supply of impulses to the muscle;
difficulty performing movements;
complete immobility of muscles.

Currently, medical scientists have become interested in myasthenia gravis due to its high incidence among children and young people. In this category of people, the disease often ends in disability.

Symptoms

Clinical manifestations of pathology depend on which muscle groups are involved in the pathological process. The severity of symptoms changes throughout the day: it intensifies after prolonged physical overexertion and decreases after a short rest. After waking up, patients feel absolutely healthy and cheerful, but after just a couple of hours these sensations disappear without a trace, replaced by malaise and weakness.

Myasthenia gravis has a progressive or chronic course with periods of remission and exacerbation. Exacerbations occur sporadically and can be long-term or short-term.

Special forms of myasthenia gravis:

A myasthenic episode is characterized by rapid and complete disappearance of symptoms without any residual effects.
When a myasthenic condition develops, the exacerbation lasts a long time and is manifested by all the symptoms that usually do not progress. At the same time, remissions are short and rare.
Under the influence of endogenous or exogenous causative factors, the disease progresses, and the degree and severity of symptoms increases. This is how myasthenic crisis occurs. Patients complain of double vision, paroxysmal muscle weakness, voice changes, difficulty breathing and swallowing, hypersalivation and tachycardia. At the same time, the face turns purple, the pressure reaches 200 mm Hg. Art., breathing becomes noisy and whistling. Tired muscles completely stop working. As a result, complete paralysis may occur without loss of sensation. Patients lose consciousness and breathing stops. Unlike paralysis, with myasthenia gravis, muscle function is restored after rest. After a couple of hours, the signs of the syndrome begin to increase again.

Myasthenia in children

Myasthenia in children is of 4 types: congenital, neonatal myasthenia, early childhood form of pathology, juvenile myasthenia.

Congenital form diagnosed in utero during a preventive ultrasound. Fetal movements are inactive. His death is possible due to respiratory failure.
In newborns pathology is detected immediately after birth. Myasthenia gravis develops in children during embryogenesis. It is inherited from sick mothers. The disease is manifested by shallow breathing, refusal to breastfeed, frequent choking, and a fixed gaze. Sick children are very weak and inactive. Infants have atrophied respiratory muscles, so they cannot breathe on their own. Newborns with congenital myasthenia often die immediately after birth.
Early childhood myasthenia gravis affects children 2-3 years old. Their vision is impaired, ptosis appears, and their eyes begin to squint. Sick babies move poorly and constantly ask to be held. They often cover their eyelids and fall when walking or running too fast.
Juvenile myasthenia found in adolescents. They complain of fatigue and visual disturbances. Schoolchildren often drop their briefcase because they cannot hold it in their hand for long. Some people can't even pedal a bicycle.

Diagnostic measures

Diagnosis of myasthenia gravis begins with examination of the patient and clarification of the medical history. Then the condition of the muscles is assessed and proceed to the basic diagnostic techniques.

Neurologists ask patients to perform the following exercises:

Quickly open and close your mouth.
Stand with your arms outstretched for several minutes.
Squat deeply 20 times.
Swing your arms and legs.
Quickly clench and unclench your hands.

A patient with myasthenia gravis will either not do these exercises or will perform them very slowly compared to healthy people. Working with the hands of the patient causes drooping eyelids. An increase in muscle weakness when repeating the same movements is the leading symptom of myasthenia gravis, detected during these functional tests.

Basic diagnostic procedures:

A test with proserin helps neurologists make a diagnosis. Since this substance is very powerful, it is used only for diagnostic purposes. Its use as a medicine is unacceptable. Prozerin blocks the enzyme that breaks down acetylcholine, thereby increasing the amount of the mediator. The medicine in this case is intended for subcutaneous administration. After the injection, wait 30-40 minutes, and then determine the body’s reaction. Improvement in the general condition of the patient indicates myasthenia gravis.
Electromyography allows you to record electrical muscle activity. Using the data obtained, disturbances in neuromuscular conduction are detected.
Electroneurography is performed if the above methods do not give clear results. The technique allows you to evaluate the speed of transmission of nerve impulses to muscle fibers.
A serological test for autoantibodies can confirm or refute the suspected diagnosis.
A blood test for biochemical parameters is carried out according to indications.
CT or MRI of the mediastinal organs can identify changes in the thymus, which often cause myasthenia gravis.
Genetic screening is designed to identify the congenital form of myasthenia gravis.

Video: ENMG in the diagnosis of myasthenia gravis

Treatment

To cope with myasthenia gravis, it is necessary to increase the amount of acetylcholine in the synapses. This is quite difficult to do. All therapeutic measures are aimed at suppressing the destruction of this mediator.

Myasthenic crisis is treated in intensive care settings using mechanical ventilation and plasmapheresis. Extracorporeal hemocorrection allows you to clear the blood of antibodies. Patients undergo cryophoresis, cascade plasma filtration, and immunopharmacotherapy. Using these procedures, you can achieve stable remission, which lasts for a year.

avoid direct sunlight,
avoid excessive physical activity,
do not take antibiotics, diuretics, sedatives, magnesium-containing drugs without a doctor’s prescription,
eat foods rich in potassium - potatoes, raisins, dried apricots,
do not be stressed.

In order for the prognosis of the pathology to be as favorable as possible, all patients must be registered with a neurologist, take prescribed medications and strictly follow all medical recommendations. This will help you maintain your ability to work and feel well for a long time.

Myasthenia gravis is an incurable disease that requires medication throughout life, with the help of which each patient can achieve sustainable remission.

Prevention and prognosis

Since the etiology and pathogenesis of myasthenia gravis are not precisely defined by scientists, effective preventive measures currently do not exist. It is known that provoking factors are injuries, emotional and physical stress, and infection. To prevent the development of myasthenic syndrome, it is necessary to protect the body from their effects.

All patients diagnosed with myasthenia gravis should be under the supervision and control of a neurologist. In addition, you should regularly measure indicators of the general condition of the body - blood glucose, pressure. This will prevent the development of concomitant somatic pathologies. Patients should not miss taking medications prescribed by the doctor and follow all medical recommendations.

Myasthenia gravis is a serious disease with high mortality. Complete diagnosis and timely treatment make it possible to achieve stable remission, and in some cases even recovery. The disease requires careful monitoring and treatment.

The prognosis of the pathology depends on the form, general condition of the patient, and the effectiveness of the therapy. The ocular form of myasthenia is best treated, but the generalized form is more difficult. Strict adherence to medical instructions makes the prognosis of the disease relatively favorable.

Video: lecture-presentation on myasthenia gravis

Video: myasthenia gravis in the program “Live Healthy!”

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, the 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 the 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 an advanced 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.

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 whose role 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 major 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

2.2 Physical examination

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 the 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 an advanced 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-Barre 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 cavities, hearts, 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 no 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)

Bibliography

Autoimmune diseases of neuromuscular transmission. In the book: A short reference book for a neurologist. – M.: “ABV-press”, 2015. – P. 129-139.
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. IN AND. Guzevoy. – M.: LLC “MK”, 2014. – P. 101-127.
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.
Aicardi J. Diseases of the nervous system in children. - T.2. – M.: Binom, 2013. – P. 940-949.
Sanadze A.G. Myasthenia and myasthenic syndromes. M.: Litterra, 2012. – 256 p.
Suponeva N.A., Piradov M.A. Myasthenia gravis. In the book: Intravenous immunotherapy in neurology. M: Hotline-Telecom, 2013. – P. 165-191.
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.
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

Pediatricians, neurologists;
Orthopedic doctors;
Exercise therapy doctors, physiotherapists,
General practitioners (family doctors);
Students of medical universities;
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 whether the interpretation of the evidence underlying the recommendations was clear.

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	Decremental response	In some patients it resembles Lambert-Eaton myasthenic syndrome, in others it manifests as mild ataxia or cerebellar nystagmus.	Mutation of the gene encoding choline acetyltransferase
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)	Repeated SPDM with single nerve stimulation	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)	Often normal ISN	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)

… VC - 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 a disease of the nervous and muscular systems, characterized by progressive weakness and pathological fatigue of various muscle groups. About 10% of patients with myasthenia gravis are children. Myasthenia gravis in children occurs in three variants.

Types of myasthenia in children

First, transient neonatal myasthenia, which occurs in children born to mothers with myasthenia gravis. These newborns have transient muscle weakness. Actually, the disease occurs in only 15% of children born to mothers with myasthenia gravis, and is apparently associated with the transplacental transfer of IgG antibodies against acetylcholine receptors. Clinical manifestations are rarely present at birth but develop within the first few days and last for several weeks. The child then makes a full recovery.

The second option - congenital myasthenia - occurs in children born to mothers who do not suffer from this disease. With this form, newborns experience general weakness, and in a later period - oculomotor disturbances. Symptoms are usually mild. Treatment is with anticholinergic drugs. Thymectomy is not indicated for any form of myasthenia gravis in young children.

The third, form of myasthenia in children - juvenile (adolescent) usually begins to appear after 10 years. Thus, according to the literature, in 74% of patients (out of 35) clinical symptoms arose after 10 years, and only in two patients - before the age of 6 years. Juvenile myasthenia gravis affects girls much more often than boys. Isolation of degrees of severity of myasthenia gravis is based on the nature and severity of symptoms.

Myasthenia gravis in children is caused by a disturbance in the transmission of neuromuscular impulses as a result of blockade of acetylcholine receptors by specific antibodies, which are detected in the serum of the majority (85%) of patients with myasthenia gravis. The immune response to acetylcholine receptors is mediated by lymphocytes. It is believed that the thymus sensitizes specific lymphocytes to produce antibodies to acetylcholine receptors. Unfortunately, the level of these antibodies, both before and after treatment, does not always reflect the severity of symptoms or response to treatment.

Treatment of myasthenia in children

Currently, there are 4 methods that can successfully treat myasthenia gravis in children:

(1) anticholinesterase drugs - pyridostigmine bromide (Mestinon) and neostigmine (Prostigmine), which accelerate the transmission of neuromuscular impulses;

(2) immunosuppression (steroids), which suppresses the immune response;

(3) plasmapheresis (removal of circulating antibodies);

(4) thymectomy, eliminating the main source of antibody production.

According to summary statistics, in 80 - 90% of adult patients with myasthenia gravis, muscle strength increases after thymectomy. As for myasthenia gravis in children, if the duration of the disease is short (less than a year), then after thymectomy it is easier to achieve improvement or even complete remission. However, even in the absence of remission, after thymectomy there is still a more pronounced positive reaction to the use of cholinesterase inhibitors.

A review of the results of treatment of myasthenia gravis in children confirms the important role of thymectomy. However, the mechanism of the effect of thymectomy on the immune system at an early age remains unclear. For this reason, it is rational to limit surgical treatment in children to those cases where the disease progresses despite the use of cholinesterase inhibitors.

Although the transsternal approach is accepted by all as the best in the treatment of thymomas, some do not consider it rational in patients with myasthenia gravis. Since not only thymectomy, but also many other factors influence the course of the disease after thymectomy, it is difficult to compare results with different approaches - cervical and transsternal. Factors that determine the outcome of surgery for myasthenia gravis in children include the severity and duration of the disease, the nature of the symptoms (generalized or ocular), and the period of observation of long-term results. In patients with severe symptoms, thymectomy is less effective. On the other hand, in patients with ocular symptoms, the results of surgical intervention are not as clear compared to those patients who had generalized symptoms before surgery. The longer the observation period after thymectomy, the more often remission of myasthenia gravis is detected in children. Currently, taking into account all the many factors influencing the results of treatment, it is difficult to talk about the advantages of a particular surgical approach in the long term.

Proponents of cervical thymectomy in the treatment of myasthenia gravis in children talk about an easier course of the postoperative period, although the results do not differ from those observed with transsternal thymectomy. Proponents argue that this approach provides the best view of the anterior mediastinum, making it possible to clearly verify complete removal of the thymus. In their opinion, relapse of myasthenia gravis in children after thymusectomy is usually associated with insufficiently complete removal of the thymus during the first operation from the cervical approach.

The article was prepared and edited by: surgeon

THE BELL