Myasthenia Gravis: Clinical Guidelines

List of Abbreviations

AChR – acetylcholine receptors

CMS – congenital myasthenic syndrome

CD – congenital defects

GC – glucocorticoids

IMV – invasive mechanical ventilation

IS – immunosorption

CT – computed tomography

CPF – cascade plasma filtration

MG – myasthenia gravis

MRI – magnetic resonance imaging

PV – plasma volume

PFE – post-activation exhaustion

PFP – post-activation facilitation

PE – plasma exchange

RNS – repetitive nerve stimulation

SFEMG – single-fiber electromyography

JMG – juvenile myasthenia

MuSK – muscle-specific kinase

Terms and Definitions

Myasthenic crisis is an acute, life-threatening condition characterized by progressive muscle weakness with the development of swallowing disorders and respiratory failure requiring invasive or non-invasive mechanical ventilation.

Condition — changes in the body resulting from the impact of pathogenic and/or physiological factors that require medical care.

Immunosorption is a method of extracorporeal hemocorrection based on the removal of target components from blood plasma—obtained after separating blood cells using centrifugal or membrane technologies—via sorption on an immunosorbent through binding to antibodies immobilized on the sorbent surface that are specific to the target component.

Instrumental diagnostics – diagnostics using various devices, apparatus, and instruments to examine a patient.

Plasmapheresis is a non-selective method of extracorporeal hemocorrection based on the complete or partial removal of plasma separated from the blood via centrifugal or membrane technology.

Plasma exchange is plasmapheresis with a plasma exfusion volume exceeding 70% of the circulating plasma volume.

Cascade plasma filtration is a selective membrane method of extracorporeal hemocorrection based on the principle of filtration and convective mass transfer of water and dissolved molecules across a semipermeable membrane via a pressure gradient, ensuring the efficient removal from blood plasma—after blood cell separation via centrifugal or membrane technologies—of high-molecular-weight large globular plasma components and other molecules and supramolecular structures larger than the albumin molecule.

Level of certainty of evidence – reflects the degree of confidence that the found effect of a medical intervention is true.

Level of recommendation certainty – reflects not only the degree of confidence in the validity of the intervention's effect, but also the degree of confidence that following the recommendations will bring more benefit than harm in a specific situation.

Working group – two or more individuals of the same or different professions working together in a coordinated manner to develop clinical guidelines and bearing joint responsibility for the results of this work.

Syndrome – a set of symptoms sharing a common etiology and pathogenesis.

Surgical intervention is an invasive procedure that may be used for diagnostic purposes and/or as a method of treating diseases.

Surgical treatment – a method of treating diseases by dividing and uniting tissues during a surgical operation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Myasthenia gravis (MG, Erb-Goldflam disease) is a classic autoimmune disease whose clinical manifestations of weakness and pathological muscle fatigability are caused by autoaggression phenomena resulting in the production of antibodies directed against various antigenic targets of the peripheral neuromotor apparatus [1,2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Myasthenia is an autoimmune disease that develops in the presence of genetic predisposition, for the realization of which environmental factors acting as triggers of the autoimmune lesion of postsynaptic membrane structures of the neuromuscular synapse are required [1,3]. Triggers can be both infectious and non-infectious factors [3]. The main mechanisms of action of trigger factors include: activation of polyclonal lymphocytes (e.g., by infectious agents); molecular mimicry—identity between portions of protein sequences of an infectious or chemical agent and autoantigens; and increased immunogenicity inducing an immune response [1]. These mechanisms ultimately trigger the development of autoimmune processes and lead to T-cell autoactivation and the production of various autoantibodies, the most significant of which are autoantibodies against the acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase (MuSK), receptor-associated lipoprotein 4 (LRP4), ryanodine receptor (RyR), titin, and other myocyte proteins. Antibodies to AChR are detected in approximately 80% of patients with the generalized form of the disease and in 50% of patients with the ocular form of myasthenia. Antibodies to MuSK and LRP4 are found in 5–8% and 2–4% of patients with the generalized form of the disease, respectively [1,4,5]. In the remaining "seronegative" patients, low-affinity antibodies to clustered AChRs are present in half of the cases [6,7].

AChR antibodies can block muscle acetylcholine receptors, enhance AChR internalization, and accelerate their degradation, though they more frequently induce complement-mediated lysis. The end results of these pathological processes are a reduction in AChR density, impaired neuromuscular transmission, and varying degrees of striated muscle function impairment [6]. Antigen expression occurs on thymic myoid cells. In patients with myasthenia, particularly young ones, there is a frequent association with thymic hyperplasia. Thymic tumors (thymomas) are detected in approximately 10% of patients with myasthenia [8]. In MuSK-positive myasthenia, complement activation and acetylcholine receptor destruction do not occur, and thymic pathology is typically not detected [9,10].

1.3 Epidemiology of the Disease or Condition

Currently, the worldwide prevalence of myasthenia ranges from 2.19 to 36.71 individuals per 100,000 population [11]. Data from epidemiological studies of myasthenia in individual regions of Russia are generally comparable to global trends. The prevalence of myasthenia in the Russian Federation ranges from 5.3 to 10.7 per 100,000 population [12–15]. Large-scale national epidemiological studies of myasthenia have not been conducted in the Russian Federation. Myasthenia can debut at any age, from early childhood to advanced old age. Depending on the age of disease onset, early-onset (<50 years) and late-onset (>50 years) myasthenia are distinguished [16]. The mean age of disease onset is 26 years in women and 31 years in men. The male-to-female ratio among patients with early disease onset is 1:3 [16]. A myasthenic crisis is observed in 15–20% of myasthenia patients at least once in their lifetime. This condition most frequently develops within the first two years after disease onset and in women of childbearing age, usually under 30. Crises in myasthenia develop in patients with generalized forms of the disease. Furthermore, in 20% of patients, a crisis may be the first symptom indicating the presence of undiagnosed myasthenia. Mortality data range from 2–5% to over 16% [17].

Regarding the pediatric population, studies conducted in Europe, Asia, and Africa demonstrate a peak incidence at 8–14 years of age with higher rates among female patients. However, the onset of myasthenia can occur at any age from 0 to 18 years [18,19].

1.4 Features of Coding the Disease or Condition

G70.0 - Myasthenia gravis

G70.2 - Congenital or acquired myasthenia

G70.8 - Other specified disorders of neuromuscular junction

G70.9 - Disorder of neuromuscular junction, unspecified

1.5 Classification of the disease or condition

In 2000, the clinical classification of the Myasthenia Gravis Foundation of America (MGFA) was adopted [20].

Note: if the patient requires tube feeding but does not require intubation, they are classified as class IVb.

Currently, a wide range of clinical, electrophysiological, and immunological criteria are used to differentiate various forms of myasthenia gravis, allowing the identification of subgroups (subclasses) of the disease [1,21,22].

A significant advantage of the MGFA classification of myasthenia gravis is the ability to analyze the severity of motor disorders while assessing the predominance and degree of involvement of extraocular, bulbar, and truncal musculature. Among the disadvantages, it is most appropriate to include the lack of information regarding the degree of possible compensation during the administration of anticholinesterase agents. At the same time, it should be emphasized that using the scale significantly facilitates the formulation of the diagnosis. For example, Myasthenia Gravis (I) – Ocular myasthenia gravis, or Myasthenia Gravis (IIIa) – Moderately severe generalized myasthenia gravis with predominant involvement of the trunk and limb muscles.

1.6 Clinical presentation of the disease or condition

Myasthenia gravis is characterized by a chronic course with periods of exacerbations and remissions. The disease can debut at any age, from early childhood to advanced old age. A combination of MG with other autoimmune diseases is frequently noted [1]. Genetic predisposition is necessary for the development of the disease, but it does not always manifest. Juvenile or childhood myasthenia gravis (JMG) occurs in pre-pubertal and pubertal patients and has clinical manifestations similar to adult myasthenia gravis.

The clinical picture of MG is based on muscle weakness and pathologically rapid fatigability of various skeletal muscle groups, which leads to difficulty or inability to perform certain movements. However, the severity of symptoms can range from mild to severe. As a rule, prolonged static tension or repeated muscle contractions lead to increasing weakness. In mild cases, symptoms may be subclinical and detected only after exertion. In such cases, clinical tests with dynamic and static loads are required for diagnosis. In more severe cases of the disease, pronounced symptoms may be present initially, and exertion will only lead to their marked increase.

Muscle weakness in myasthenia gravis is characterized by: 1) selective (predominant) involvement of individual muscle groups; 2) discrepancy between the localization of weakness and the innervation zone of individual nerves; 3) lability of clinical manifestations of weakness; 4) reduction of weakness after administration of anticholinesterase agents [23].

Often the first complaints are double vision and drooping eyelids, difficulty chewing and swallowing, a decrease in voice loudness during prolonged conversation, and increased fatigability of the arm or leg muscles during prolonged exertion. A dynamic nature of these symptoms with their progression throughout the day is typical. Fluctuations of the disease are observed over weeks or months. In some cases, severe exacerbations (myasthenic crisis) may occur [1,22].

When analyzing anamnestic data, signs indicating the presence in the recent past of short-term episodes of weakness and fatigability, which completely or partially regressed spontaneously or during non-specific treatment, are often present. In 90% of cases, these episodes are associated with extraocular muscle involvement and manifest as diplopia and eyelid ptosis. Much less frequently, these are episodes of bulbar disorders or truncal muscle weakness [1]. In MuSK-positive myasthenia gravis, there is a tendency to develop bulbar and respiratory disorders, and myasthenic crises frequently occur [9,24].

Approximately 2/3 of patients with the ocular form of myasthenia gravis develop the generalized form within the first two years. In the remaining patients, the disease progresses to generalized myasthenia gravis in only 10–20% of cases [1]. Mortality in myasthenia gravis has significantly decreased recently and is about 5% [16,25]. Clinical remission can be achieved in the majority of patients; however, many patients remain dependent on maintenance therapy throughout their lives [1,22,26]. In some cases, a refractory course of the disease is possible, which is defined as the absence of a positive effect or worsening of the condition after taking GCS and at least two other immunosuppressive drugs (in adequate doses and for a sufficient time), with persistent symptoms or side effects limiting the ability to function [27].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of MG is based on four main criteria [23]:

1. Clinical: selective involvement of individual muscle groups (blepharoptosis, external asymmetric ophthalmoparesis, bulbar muscle involvement, proximal limb muscle weakness);

2. Immunological: testing for antibodies against acetylcholine receptors and MuSK;

3. Electrodiagnostic: detection of a decrement in M-wave amplitude during low-frequency nerve stimulation, single-fiber electromyography (jitter analysis);

4. Pharmacological: test with #neostigmine methylsulfate.

2.1 Complaints and Anamnesis

Comments: patients with MG complain of eyelid drooping, double vision, speech and swallowing disorders, inability to raise arms up, difficulty washing and combing hair, shaving and hanging laundry [32], and difficulty climbing stairs. At disease onset, 62.8% have only ocular symptoms (ptosis, diplopia, ophthalmoparesis). In 14.8% of cases, myasthenia gravis debuts isolated with bulbar disorders, and in only 4.8% of patients does MG begin with isolated limb weakness. Isolated weakness of the neck extensor muscles is observed in 1.3% of cases, and MG debut with respiratory disorders is noted in 0.5% of cases. If the disease debuted with ocular symptoms, generalization of MG most often occurs in the first two years of the disease [33].

Comments: intake of penicillamine** can rarely cause myasthenia gravis [29].

Comments: myasthenia gravis is one of the rare neurological complications of certain monoclonal antibodies (immune checkpoint inhibitors) [35,36].

2.2 Physical Examination

Comments: clinically, MG manifests as muscle weakness and pathological muscle fatigability syndrome (increased weakness with physical exertion and reduction after rest and sleep) [37]. Myasthenia is characterized by selective involvement of certain muscles while sparing others: ptosis, ophthalmoparesis, bulbar symptoms, and limb muscle weakness are common, and respiratory disturbances may occur [23,30,33]. A characteristic feature is also the mismatch between the localization of weakness and the innervation zones of individual nerves [23].

In the ocular form, extraocular muscles are affected, usually asymmetrically, with typical symptoms of periodic upper eyelid drooping (ptosis) and double vision (binocular diplopia). Pupil size and pupillary reactions are preserved. Ptosis in the ocular form may be isolated. Simpson's sign may be observed (ptosis increases when looking upward) [40]. Cogan's lid twitch sign for the diagnosis of myasthenia has a sensitivity of 50% to 99% and a specificity of 75% to 100% (after looking down for 10–15 seconds, a brief twitch of the affected upper eyelid occurs when looking straight ahead). Detection of Cogan's sign increases suspicion of myasthenia but is not pathognomonic [41,42]. In the generalized form, there is also symmetric impairment of facial expression, weakness of the masticatory muscles, and involvement of the peribulbar muscles (dysarthria that worsens with speech load, nasal speech, dysphonia, dysphagia, often with nasal regurgitation of liquids). Bulbar and respiratory disturbances can be life-threatening and require intensive care [37,43]. In addition to the face, the most commonly affected muscles in myasthenia are the shoulder abductors, hip flexors, and neck muscles [41]. There is no correlation between muscle weakness and disease duration [32]. Tendon reflexes are preserved in myasthenia; sensory and coordination disturbances are absent. Pelvic organ dysfunction is generally absent. For seropositive myasthenia with AChR antibodies, muscle atrophy is not characteristic, whereas in myasthenia with MuSK antibodies, atrophy of the tongue and other muscles may be observed [43]. Clinical evaluation of respiratory functions includes assessing chest excursion, cough strength, and respiratory rate.

Comments: the MGFA clinical classification was developed to identify subgroups of MG patients with different clinical features or disease severity; it is somewhat subjective regarding the distinctions between mild, moderate, and severe weakness [33], nevertheless, the use of the MGFA classification is convenient in clinical practice.

2.3 Laboratory Diagnostics

Comments: a positive AChR antibody result in combination with a typical clinical picture and pathological muscle fatigability syndrome confirms the diagnosis of myasthenia [37]. A negative AChR antibody result may be observed in seronegative myasthenia; in this case, testing for MuSK antibodies is necessary, and other diseases whose clinical picture may resemble myasthenia should be ruled out. In rare cases, a false-positive AChR antibody result may occur [53]. Diagnosing MG in children is more challenging, partly due to a higher percentage of seronegative cases and the frequent need for differential diagnosis with congenital myasthenic syndromes.

Comments: a positive MuSK antibody result proves the presence of MuSK antibody-associated myasthenia. The specificity of MuSK antibodies is very high (97–98%), yet it must be remembered that a false-positive result is possible in 1.9% of cases [54,55]. Double-seronegative myasthenia (in which both AChR and MuSK antibodies are absent) occurs in approximately 15% of generalized and 50% of ocular myasthenia cases [56]. Patients with double-seronegative myasthenia may have low-affinity AChR antibodies (not detected by routine testing methods), as well as antibodies to LRP4, agrin, and cortactin [45,56–58].

In the absence of both AChR and MuSK antibodies, differential diagnosis must be performed with other conditions presenting with oculomotor, bulbar disorders, and proximal flaccid tetraparesis; primarily Lambert-Eaton syndrome, botulism, congenital myasthenic syndromes, thyroid eye disease, myopathies, and motor neuron disease with bulbar onset [23].

Comments: congenital myasthenic syndromes (CMS) represent a heterogeneous group of disorders characterized by impaired neuromuscular transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction. As of January 2023, 35 genes have been identified whose mutations can lead to CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The initial manifestations of the disease most commonly appear at birth or in the first years of life, although in some cases, onset may occur in adolescence or adulthood. Clinical manifestations of CMS are heterogeneous. Symptoms may vary even within the same family. Clinical features of CMS are characterized by muscle fatigability, muscle weakness, muscle hypoplasia, and minor facial anomalies such as low-set ears and a high-arched palate in some patients. Unlike MG, diurnal fluctuations in muscle strength and muscle fatigability are not always observed in CMS. Some patients with CMS exhibit pronounced diurnal fluctuations in muscle strength. Diurnal fluctuations in external ophthalmoparesis are associated with diplopia in MG, but not always in CMS. Some lack ocular symptoms, and they are referred to as limb-girdle CMS. In the majority of patients with CMS, the disease develops before age 2, but in some patients, symptoms develop immediately after birth and then temporarily remit until adolescence or adulthood. Including these neonatal transient patients, CMS can manifest at any age, including adolescence and adulthood. Some patients exhibit psychomotor developmental delay [60].

2.4 Instrumental Diagnostics

2.4.1 Electrodiagnostic studies

Comments: supramaximal indirect nerve stimulation at a frequency of 2–5 Hz with 5–10 stimuli is indicated (stimulation at 3 Hz with 5 stimuli is most commonly used). The post-activation facilitation (PAF) test is performed after isometric contraction of the test muscle for 10 seconds (up to 1 minute), and the post-activation exhaustion (PAE) test is performed 1–5 minutes after isometric contraction. An interval of 2 minutes is sufficient to assess PAE [66]. Myasthenia is characterized by a hyperbolic or U-shaped M-wave amplitude decrement, with the amplitude decrement being most pronounced between the 1st and 2nd stimuli and less pronounced between the 4th and 5th stimuli. For most muscles, a decrement of more than 10% is considered pathological [67]. In the PAF test, the decrement decreases or resolves, and in the PAE test, it increases again [61]. The choice of muscle depends on the clinical picture and is performed on a clinically weak muscle [22,33]. In the ocular form of myasthenia, it is advisable to test the orbicularis oculi muscle. In the presence of bulbar symptoms, testing the digastric muscle is indicated. In generalized myasthenia, the deltoid and trapezius muscles are the most sensitive. Hand muscles are the least sensitive and should be avoided when selecting a muscle for testing. The sensitivity of low-frequency repetitive nerve stimulation in generalized MG is 71.6%, and in the ocular form, 38.5% [68]. Using low-frequency repetitive nerve stimulation for the diagnosis of myasthenia in an inpatient setting may be a more useful diagnostic method than testing for AChR antibodies, as antibody results are significantly delayed compared to repetitive nerve stimulation [68].

Comments: tetanization is a painful procedure that is poorly tolerated by patients, so it should be performed strictly according to indications. Tetanization is not required for the diagnosis of myasthenia gravis, but is necessary for differential diagnosis with a presynaptic lesion level (Lambert-Eaton myasthenic syndrome, botulism) [67]. A presynaptic lesion during low-frequency repetitive nerve stimulation can be suspected when: 1. there is a combination of low amplitude of the first M-wave and the presence of an M-wave amplitude decrement (characteristic of both Lambert-Eaton syndrome and botulism, and can sometimes be observed in myasthenia gravis); 2. the amplitude of the first M-wave increases during post-activation potentiation (PAP) by more than 100% compared to the amplitude of the first M-wave in the pre-activation series (characteristic of Lambert-Eaton syndrome, sometimes of myasthenia gravis, but not of botulism). During high-frequency repetitive stimulation (muscle tetanization at 50 Hz), myasthenia gravis reveals an M-wave amplitude decrement, whereas presynaptic disorders (Lambert-Eaton syndrome and botulism) reveal an M-wave amplitude increment. The optimal stimulation frequency for the differential diagnosis of myasthenia gravis and Lambert-Eaton syndrome is 50 Hz, and for myasthenia gravis and botulism, it is 20 Hz [69].

Comments: the sensitivity of single-fiber electromyography ranges from 77% to 96% according to various estimates [70]. The sensitivity of SFEMG in ocular myasthenia is 80%, and in generalized myasthenia 95-99% [71]. Jitter testing using a concentric needle electrode has been validated [72]. The jitter testing technique is extremely labor-intensive and complex, and is mostly performed in specialized centers. If the diagnosis of myasthenia gravis is confirmed by other methods (presence of AChR or MuSK antibodies, a positive pharmacological test with #neostigmine methylsulfate**), jitter testing is not required. The need for the test arises in cases of differential diagnosis when other methods do not allow a definitive diagnosis to be established. Jitter testing can be used for prognostic purposes [62]. Jitter is not specific to myasthenia gravis and is also increased in other synaptic disorders, reinnervation, and a number of myopathies. Single-fiber EMG has a high negative predictive value in identifying patients without myasthenia gravis [56,70].

2.4.2 Anterior mediastinal imaging

Comments: imaging of the anterior mediastinum allows the detection of thymic hyperplasia or thymoma. Mediastinal CT with intravenous bolus contrast enhancement is preferred over MRI [75,76]. The frequency of repeat imaging of the anterior mediastinum is determined individually. As a rule, in the absence of changes, a repeat study is not required, but may be performed after several years of follow-up. The need for imaging after thymectomy or after removal of a thymoma is determined by a thoracic surgeon.

Comments: mediastinal MRI is usually not used to evaluate thymic tumors, although it is sufficiently informative and can be performed instead of mediastinal CT if CT is unavailable or if the patient has an allergy to iodine-containing contrast media or renal failure [76].

Comments: thymic hyperplasia is not visualized on targeted chest radiography [79], therefore the use of targeted chest radiography is limited in myasthenia gravis. Radiography can be used as a primary diagnostic method for thymic tumors [76].

2.5 Other Procedures

Comments: there are three routes of administration: subcutaneous [23], intramuscular [81], and intravenous [42]. #Neostigmine methylsulfate** is administered subcutaneously or intramuscularly at a dose of 1.5 ml of a 0.05% solution for a patient weighing 50-60 kg, 2.0 ml for a patient weighing 60-80 kg, and 2.5 ml for a patient weighing 80 to 100 kg. In children, the dose is 1.0 ml. During the test, 15% of patients show complete compensation (increase in muscle strength up to 5 MRC points), 75% show incomplete compensation (increase in strength by 2-3 points, but not reaching 5 MRC points), partial compensation (strength increased by 1 point in some muscles, while remaining unchanged in other tested muscles), and no compensation. Complete and incomplete compensation of motor disorders is assessed as a positive test. Partial compensation is considered doubtful, and absence of compensation is considered negative [23].

The pharmacological test with anticholinesterase agents causes cholinergic side effects and may be associated with certain risks: bradyarrhythmia up to asystole and cardiac arrest, bronchospasm, seizures, and transient ischemic attack. It should be performed by a specialist in settings capable of responding to such effects, with monitoring of heart rate and blood pressure [80,81]. Therefore, it is preferably performed in a multidisciplinary facility or specialized center.

Comments: the ice pack test is a simple and cost-effective bedside test. The specificity of the test ranges from 62.5% to 95% according to various studies. The test can be performed on both eyes or on the eye with the most pronounced ptosis, with an ice pack applied for 2 minutes. The ice pack test is considered positive if the eyelid elevates by more than 2 mm [83–85]. The ice pack test has a high negative predictive value (a negative ice pack test rules out myasthenia gravis with a 94% probability) [85].

Comments: a patient with a clinical picture of myasthenia gravis, electrodiagnostically proven neuromuscular transmission disorders (repetitive nerve stimulation, SFEMG), but without AChR and MuSK antibodies and without a positive response to pathogenetic therapy, should be referred for genetic testing [23,42,80–82].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment of myasthenia gravis consists of symptomatic and pathogenetic therapy. Symptomatic therapy includes anticholinesterase drugs. Pathogenetic treatment methods include the administration of GCS, antineoplastic drugs and immunomodulators, normal human immunoglobulins, plasmapheresis, monoclonal antibodies, as well as surgical treatment—removal of the thymus gland (thymectomy). In children, treatment methods are similar to those used in adults and are usually very effective with a high rate of achieving remission.

3.1 Conservative Treatment

3.1.1. Symptomatic treatment of MG

Anticholinesterase drugs, such as pyridostigmine bromide**, are used as medications that temporarily increase the amount of acetylcholine in the synaptic cleft and thereby improve neuromuscular transmission. 

Comment: the initial dose is 30 mg up to 4 times a day for 2–4 days. If well tolerated and in the absence of adverse events, the single dose is increased to 60 mg up to 4 times a day for 5 days. If necessary, the single dose can be increased to 90 mg up to 4 doses per day [88]. The single dose of pyridostigmine bromide** can be increased up to 120 mg if necessary, but this increases the risk of adverse effects. Overdose of anticholinesterase drugs can lead to a decrease in the drug's efficacy and worsening of myasthenia gravis up to the development of a cholinergic crisis. Therefore, when selecting the dosage regimen of anticholinesterase drugs, it is necessary to regularly monitor muscarinic and nicotinic cholinergic adverse effects (abdominal discomfort and pain, diarrhea, rhinorrhea, bronchorrhea, decreased blood pressure, muscle twitching, cramps, etc.) and, if they appear or, moreover, worsen, timely adjust therapy by reducing the dosage or frequency of administration [86]. The optimal dose is the one that provides a balance between pronounced clinical improvement and minimal cholinergic effects [21].

In seronegative MG with anti-MuSK antibodies, the response to therapy with anticholinesterase drugs may be less pronounced than in patients with the AChR-positive form of the disease [21,24].

In the ocular form of myasthenia gravis, a limited effect of anticholinesterase drugs may also be observed. At the same time, ptosis responds better to therapy, while the range of motion of the eyeballs is often not fully restored upon drug administration [89].

When disease remission is achieved against the background of pathogenetic treatment methods, the patient's need for anticholinesterase drugs may decrease. In such cases, it is necessary to adjust the intake of anticholinesterase drugs according to need [28].

Comment: in the treatment of myasthenia gravis in children, the initial dose of anticholinesterase drugs is 0.5–1 mg/kg every 5–6 hours during waking hours. The maximum effect occurs in 1–2 hours, with the duration of action ending in 5–8 hours. The maximum dose in children is 7 mg/kg/day, but it must be evaluated for each patient. High doses will not lead to improvement; on the contrary, the risk of cholinergic reactions (signs of overdose) increases. Dose adjustment is necessary during the course of treatment. Ultimately, the dose of anticholinesterase drugs is selected individually for each patient depending on tolerability and sufficient efficacy. Patients, especially adolescents, and their parents must actively cooperate with the attending physician and adjust the administration schedule and dosage of anticholinesterase drugs throughout the day depending on symptoms [18,90,91].  

3.1.2. Pathogenetic treatment

First-line pathogenetic therapy drugs include GCS, which exert a multifaceted inhibitory effect on the immune response.

Comment: the therapeutic dose of #prednisolone** ranges from 0.75–1.5 mg/kg of body weight (60–100 mg) [88]. The drug is prescribed on an alternating-day schedule (every other day). Initially, the drug can be prescribed at the therapeutic starting dose [6]. At the same time, in some cases, prescribing high doses of GCS during the first two weeks may worsen the course of MG [93], which makes it advisable to start therapy with #prednisolone** at low doses (5–25 mg) with gradual titration to the therapeutic dose [6,86,88]. Symptom relief in most cases begins to be observed within 2–6 weeks after starting therapy [86]. A distinct clinical effect is achieved within 3 months [88]. Sustainable disease remission with GCS therapy is achieved in 70–80% of cases [86]. After achieving a clinical effect, the dose is gradually reduced until complete discontinuation or to low maintenance doses, which the patient takes for a long time.

GCS therapy is associated with a large number of potential side effects, such as weight gain, diabetes mellitus, hypertension, peptic ulcer disease of the stomach and duodenum, cataract, glaucoma, osteoporosis, and psychiatric disorders. Therefore, during long-term therapy with these drugs, patient monitoring by relevant specialists is indicated for the prevention, early detection, and management of complications [88,94].

In juvenile myasthenia gravis (JMG), therapy with #prednisolone** is administered at 1 mg/kg/day orally as a single morning dose after a meal. The most rational approach is alternating-day administration for mild to moderate myasthenia, as well as severe forms without pharyngeal and respiratory muscle involvement.

In severe myasthenia gravis, daily administration of GCS is required, alternating a full dose and half the daily dose every other day until stabilization of bulbar and respiratory disorders is achieved; thereafter, a transition to an alternating-day regimen is possible.

This approach significantly reduces the severity of GCS side effects and helps avoid the aggravation of muscle weakness during the first 7–10 days of corticosteroid therapy. Further administration of GCS on an alternating-day schedule is continued until a state is reached where no exacerbation of muscle weakness is observed on the off-day, indicating the restoration of sufficient compensatory mechanisms at the neuromuscular junction and the development of a sustained anti-inflammatory effect of GCS. Subsequently, GCS therapy is continued until complete compensation of clinical manifestations. Dose reduction, down to discontinuation (if possible), must be carried out slowly and cautiously. The maintenance dose is selected individually.

Starting glucocorticoid treatment prior to thymectomy helps reduce surgical risks and stabilize the patient's overall condition in the postoperative period while awaiting the effect of the surgery.

In addition to oral administration, parenteral administration of GCS is also possible. The decision on the route of GCS administration should be made by the attending physician individually for each patient, depending on the clinical situation at the time of the decision.

The use of GCS in ocular myasthenia gravis in children remains controversial, especially in the prepubertal age, due to the possibility of spontaneous remission, a more benign course, a lower rate of progression to the generalized form, and the risk of growth retardation. However, in case of a poor response to anticholinesterase drugs, GCS can be used as good symptom control is achieved at relatively low doses. A double-blind randomized study in adults demonstrated the benefit of GCS in ocular myasthenia gravis [18,90,91,95,96].

Second-line pathogenetic therapy drugs include antineoplastic agents and immunomodulators.

Comment: the typical initial dose of azathioprine** is 50 mg daily for one week, then it is increased by 50 mg each week to a therapeutic dose of 2-3 mg/kg daily, divided into 2-3 doses. Azathioprine** has a delayed onset of effect. A distinct clinical improvement is observed no earlier than 4-6 months after starting the drug [98]. After achieving remission, it is advisable to continue therapy for at least two to three years, after which, under careful monitoring to detect relapses, a gradual dose reduction of azathioprine** to complete withdrawal can be initiated [26].

The most frequent side effects of azathioprine** are leukopenia and hepatotoxicity. Regular complete (clinical) blood counts (formed elements), as well as blood urea testing, determination of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase activity in the blood, and total bilirubin blood testing are required. At the beginning of therapy while increasing the azathioprine** dose to therapeutic, laboratory monitoring is performed weekly, and then monthly. If laboratory changes are present, the dose of the drug should be reduced [88, 94].

In 10-20% of cases in the early stages of treatment (first 1-2 weeks), intolerance in the form of a specific drug reaction may occur, manifesting as fever and malaise, which requires immediate and permanent discontinuation of the drug [94].

In the treatment of JMG, the prescription of azathioprine** is also advisable in case of an insufficient (or absent) response to GCS (or in case of limited possibility of using GCS, for example, in diabetes) before thymectomy or in the absence of effect after thymectomy. In such a situation, azathioprine** is the first-line drug of choice. The starting dose is 1 mg/kg/day 1-2 times a day, with a gradual increase of 0.5 mg/kg/day every 2-4 weeks up to a maximum dosage of 2.5 mg/kg/day. The maintenance dose of 2.5 mg/kg/day is maintained for 10-12 months, and then very slowly reduced to 1 mg/kg/day. The clinical effect should be expected no earlier than 3 months after starting administration. The duration of therapy can be up to 2 years. In case of side effects (fever, nausea, abdominal pain, leukopenia), immediate discontinuation of the drug is required [18, 90, 91, 99].

Comment: the therapeutic dose of #mycophenolate mofetil** is 1000-2000 mg daily in two doses [94, 100, 101]. The maximum clinical effect develops with a treatment duration of 13 months or more [100–102].

Considering the risk of adverse events such as leukopenia, anemia, pancytopenia, and agranulocytosis, it is advisable to perform a complete (clinical) blood count twice in the first month of treatment, then monthly [94, 103].

Considering the potential teratogenic effect of #mycophenolate mofetil**, it is advisable to avoid prescribing the drug to women planning pregnancy or who are pregnant. In case of unplanned pregnancy, discontinuation of the drug is advisable [104].

Given that #mycophenolate mofetil** has been scarcely studied regarding JMG, it should be considered only as a second-line drug and used if all other therapies are ineffective or contraindicated. Common side effects include nausea, vomiting, diarrhea, and less frequently leukopenia. There is also a risk of progressive multifocal leukoencephalopathy.

The drug should be prescribed to pediatric patients at a dosage of 600 mg/m² per day. The maintenance dose is 1000-1500 mg in 2 daily doses. The recommended duration of administration is 2-12 months [18, 90, 91, 99].

Comment: for patients over 18 years of age the initial dose of #cyclosporine** is 3-4 mg/kg per day, divided into 2 doses [94, 109, 110]. A distinct clinical effect in most patients is observed after 6 months, although in some cases improvement may be noted earlier – starting from 3 weeks of drug administration [105]. After achieving stable clinical improvement, the dose can be reduced to 2-2.5 mg/kg per day [111].

The most frequent side effects of #cyclosporine** are nephrotoxicity and arterial hypertension. Regular blood creatinine testing and blood pressure monitoring are necessary [94].

In pediatric practice, the use of #cyclosporine** may also be considered in the absence of effect after thymectomy, on the background of azathioprine** therapy, and generally in refractory JMG. #Cyclosporine** is introduced into the treatment regimen as a second drug together with GCS. The initial dose is calculated at 2.5 mg/kg/day, divided into 2 doses. The blood concentration of #cyclosporine** should be monitored once a week in the first month of administration, and thereafter, upon reaching a working concentration of 100-150 ng/ml, once a month. Monthly monitoring of blood urea and creatinine is also necessary, as #cyclosporine** is nephrotoxic. The duration of administration, if well tolerated, can reach 1-2 years. Upon achieving a good clinical effect on the background of #cyclosporine** therapy, a gradual reduction of the GCS dose should be carried out, down to discontinuation (if possible) [90, 91, 108].

Comment: for patients over 18 years of age, the initial dose is 10 mg/week with a gradual increase to 20-25 mg/week over 2 months [94, 102]. A stable effect is noted in most cases after 10-12 months of drug administration [112]. After stabilization of the condition, a slow and careful dose reduction is possible [110].

The most frequent adverse effects of #methotrexate** are hepatotoxicity, ulcerative stomatitis, leukopenia, anemia [111]. Regular complete blood count (CBC), determination of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin in the blood are indicated. For the prevention of stomatitis in patients over 18 years of age, it is advisable to prescribe folic acid** at a dose of 1 mg/day [94]. Pulmonary fibrosis is considered a rarer complication, which requires caution when prescribing the drug to patients with pulmonary diseases [94]. Considering that #methotrexate** has teratogenic effects, its use should be avoided in pregnant women or those planning pregnancy, during pregnancy, and breastfeeding. In addition, the drug has mutagenic effects, so before prescribing it to men, it is advisable to discuss the possibility of sperm cryopreservation [110].

For the adult population, Level of Recommendation A (Level of Evidence – 2).

For the pediatric population, Level of Recommendation C (Level of Evidence – 4).

Comment: for patients over 18 years of age, the initial daily dose of #tacrolimus** is 3 mg/day (divided into two doses). Subsequently, depending on the clinical effect, blood concentration of the drug, and complications, the daily dose can be reduced to 2 mg or increased to 4 mg. The clinical effect begins to appear within 1–3 months, and the maximum effect is achieved 6–12 months after the initiation of therapy [114–119].

For pediatric patients, #tacrolimus** is prescribed at an initial daily dose of 0.05 mg/kg/day (divided into two doses). If the effect is insufficient, the dose can be increased up to 0.1 mg/kg/day (maximum <4 mg/day) [118].

The most frequent adverse effects developing with #tacrolimus** intake are elevated glucose, neutrophilia, hypomagnesemia, hyperlipidemia, respiratory infections, arterial hypertension, gastrointestinal disorders, and less frequently, neurological manifestations such as tremor and paresthesia. Adverse effects are reversible and resolve upon dose reduction or drug discontinuation [119]. When prescribing the drug, regular complete blood count (CBC), blood glucose, blood cholesterol, blood triglycerides, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin, blood urea and creatinine, blood potassium, blood sodium, electrocardiogram (ECG), and blood pressure monitoring should be performed [119,120]. It is advisable to regularly monitor the blood concentration of tacrolimus, the target values of which should be 4.0–10.0 ng/mL. Within this concentration range, a clinical effect is observed with a minimal risk of adverse events [121]. It must be taken into account that concurrent administration of #tacrolimus** with drugs affecting CYP3A4 cytochrome activity may alter plasma concentrations of tacrolimus [122].

Comment: for patients over 18 years of age, the universal administration protocol for #normal human immunoglobulin** is a total course dose of 2 g/kg, administered daily for 5 days (0.4 g/kg per day). Clinical improvement develops within 10–14 days and persists for 4–18 weeks [114–119].

The infusion should be started at a rate of 0.5–1 mL/kg/h for the first 15–30 minutes. In the absence of adverse reactions, the rate can be gradually increased every 15–30 minutes to a maximum of 3–6 mL/kg/h [131]. The most frequent adverse effects of normal human immunoglobulins are fever, nausea, headache, and local skin reactions, which are generally mild. In rare cases, serious adverse effects such as acute renal failure, hemolytic anemia, severe allergic reactions, and thromboembolic complications are possible [123,131,132].

In juvenile myasthenia gravis (JMG), normal human immunoglobulins should also be used in the treatment of exacerbations or for stabilization prior to thymectomy. It is also effective as maintenance therapy. The dose of #normal human immunoglobulin** in JMG is 1 g/kg/course administered via IV infusion [133–135].

Comment: the drug is administered intravenously as an infusion over 35 minutes. Currently, the recommended dosing regimen is 900 mg on the first day of treatment, repeated weekly for the first four doses. From week 4, the dose is increased to 1200 mg and administered every two weeks for maintenance [136,140]. The initial effect can be observed as early as the 1st month of therapy and in most cases appears within 3 months from the start of treatment [136].

The most frequent adverse events occurring during eculizumab** treatment include headache, upper respiratory tract infections, and nasopharyngitis. The most serious potential complication is meningococcal infection [136]. Administration of the drug is contraindicated in patients with a current N. meningitidis infection, as well as in patients who are not vaccinated against meningococcal infection, unless the risk of delaying eculizumab** treatment outweighs the risk of developing meningococcal disease [136]. Patients must be immunized with meningococcal vaccines (J07AH Meningococcal bacterial vaccines) at least 2 weeks prior to receiving the first dose of eculizumab**, and if eculizumab** must be started immediately, systemic antibacterial prophylaxis should be administered to patients for 2 weeks [136].

Comment: the dosage depends on body weight. On the first day of therapy, the initial dose is administered: for patients with a body weight of ≥40 to <60 kg – 2400 mg, for patients from ≥60 to <100 kg – 2700 mg; for patients with a body weight of more than 100 kg – 3000 mg. Subsequently, on day 15, and then repeating every 8 weeks, a maintenance dose is administered, amounting to 3000 mg for patients from 40 to <60 kg, 3300 mg for patients from ≥60 to <100 kg, and 3600 mg for a body weight of more than 100 kg [141,144]. The initial effect may be observed as early as 2–4 weeks after the start of therapy [142]. The most frequent adverse effects of therapy are headache, diarrhea, and nausea [143]. A serious potential complication of ravulizumab treatment is meningococcal infection; to reduce the risk of its development, all patients must be vaccinated against meningococcal infection within 3 years of therapy or 2 weeks before the start of treatment. In cases where ravulizumab therapy is initiated less than 2 weeks after vaccination, the patient is prescribed a prophylactic course of systemic antibacterial drugs for 2 weeks following vaccination [142,144].

Comment: in patients over 18 years of age, the most common administration regimen for #rituximab** is 375 mg/m² weekly for 4 weeks; a positive effect may be observed in 1–3 months. Administration may be repeated if necessary after 6 months [94,145–147].

Administration of the drug is carried out under hospital supervision with the necessary facilities for resuscitation measures available. The most frequent adverse effects include skin rash, pruritus, sore throat, headache, nausea, chills, arterial hypotension; allergic reactions, anemia, leukopenia, thrombocytopenia [94,148,149]. One of the rare but potentially fatal complications of #rituximab** therapy is progressive multifocal leukoencephalopathy associated with JC virus reactivation (a DNA-containing virus from the Polyomaviridae family) [150]. Patients over 18 years of age are indicated to receive oral #paracetamol** 1000 mg to prevent headache and #diphenhydramine** 25 mg to prevent skin pruritus before each infusion of the drug #rituximab** [94,148]. During the course of treatment, it is advisable to perform a general (clinical) blood count monthly [94].

In juvenile myasthenia gravis (JMG), the use of #rituximab** is also possible in cases of a refractory course of the disease, lack of effect from GCS after thymectomy, and ineffectiveness of other cytotoxic drugs. Pediatric literature on #rituximab** generally shows favorable results in the treatment of refractory JMG. Dosing regimen: 375 mg/m² once a week for 4 weeks. The duration of treatment is determined by the clinical picture and may range from 1 to 2 years (2–3 courses) [18,151–154].

3.2. Extracorporeal hemocorrection methods

The use of non-selective plasmapheresis (plasma exchange - PE), semi-selective plasmapheresis (cascade plasma filtration - CPF), and selective apheresis (immunosorption - IS) is indicated as pathogenetic therapy for myasthenia gravis in patients with a severe exacerbation of the disease in the presence of life-threatening symptoms, such as pronounced bulbar disorders and progressive respiratory failure, in case of resistance to baseline pathogenetic therapy, or as preoperative preparation before thymectomy [155–158]. PE/CPF/IS can be used as first-line therapy for MG, as monotherapy, or in combination with other pathogenetic therapy methods (glucocorticoids, normal human immunoglobulins, antitumor drugs, and immunomodulators). PE, CPF, and IS have demonstrated equal efficacy in the treatment of MG [159,160]. There are two regimens for PE/CPF/IS in MG: 1) short-term treatment - used for myasthenic crises and MG exacerbations with life-threatening symptoms (severe generalized muscle weakness, pronounced bulbar disorders, progressive respiratory failure). It is also used for preoperative preparation before thymectomy. The course of short-term treatment is 3-6 sessions performed daily or every other day for 10-14 days. Daily and alternate-day protocols have equal efficacy and safety [127]. Clinical improvement usually develops within 1-12 days and persists for 4-12 weeks [161]. 2) long-term treatment - used to maintain partial or complete remission of MG in patients with frequent exacerbations (more than 2 exacerbations per year), in case of resistance or intolerance to drug therapy, or as an adjunct to corticosteroid therapy [162]. There are several long-term treatment regimens: 1 session per week, 1 session every two weeks, or 1 session every 4-6 weeks until clinical symptoms improve [162]. When performing PE/CPF/IS, mild to moderate complications may develop, such as hypotension symptoms (presyncope/syncope, tachycardia), citrate reactions (paresthesias, muscle cramps, muscle twitches, hypocalcemia), headache, nausea, and rare severe complications: allergic (anaphylactic shock, bronchospasm), thrombotic (deep vein thrombosis, pulmonary embolism), cardiac (ventricular arrhythmia, acute left ventricular failure), infectious (bacteremia, sepsis) complications [123–125,161,163,164]. 

Comment: initiating plasma exchange at an early stage of exacerbation yields significantly better clinical results and shortens the duration of hospitalization compared to later treatment initiation. Delaying plasma exchange therapy by more than 2 days from the moment of hospitalization can lead to an increased rate of complications and mortality, so prompt initiation of treatment is justified [165]. It is advisable to initiate or continue immunosuppressive therapy concurrently with the start of plasma exchange to control MG exacerbations and prevent a rebound effect after plasma exchange [156,166]. Plasma exchange and normal human immunoglobulins are equally effective in treating MG exacerbations, except for the MuSK antibody-positive form of MG, where plasma exchange is superior to normal human immunoglobulins. The choice of treatment method depends on the patient's comorbidities, tolerability, and the availability of methods [10,124,127,167–170]. For elderly individuals and those with complex comorbidities, including acute respiratory failure, it is preferable to use intravenous normal human immunoglobulins [165]. Technical specifications: the perfused plasma volume per 1 session is 1–1.5 circulating plasma volumes (CPV); the replacement fluid consists of polyelectrolyte solutions, albumin**, fresh frozen plasma.

Indications for plasma exchange in JMG are also similar to the indications for the administration of normal human immunoglobulins – primarily in the treatment of exacerbations and ensuring stability prior to surgery. Favorable results have also been noted in MuSK antibody-positive JMG. A typical course of treatment consists of 3–5 exchanges every other day and requires the placement of a central venous catheter. For 1 session, plasma exchange should be at least 1 CPV. The main limiting factor in young children is inadequate venous access, so intravenous administration of normal human immunoglobulins may be more practical in this situation [10,124,135].

Comment: the advantages of this method include high selectivity, a reduction in the volume of plasma-substituting solutions, a lower risk of allergic and infectious complications, and an immunomodulatory effect. CPF significantly shortens hospitalization times, decreases the number of acetylcholine receptor antibodies, and reduces the time required to achieve remission [172]. Daily CPF sessions may be more effective in treating patients with late-onset MG [170]. CPF combined with oral glucocorticoids exerts a more pronounced therapeutic effect compared to glucocorticoid monotherapy [171]. Technical specifications: the perfused plasma volume per 1 session is 1–1.5 CPV; plasma fractionators with small or medium pore size filters (10 nm, 20 nm) are used; the replacement fluid is albumin** or fresh frozen plasma.

Comment: the advantages of this method include high selectivity (immunoglobulins, immune complexes, and blood clotting factors are adsorbed to a lesser extent than during plasma exchange), a low incidence of adverse effects, and no need to use plasma-substituting solutions. The use of CPF and IS shortened the time to onset of remission compared to normal human immunoglobulins [173,174]. Technical specifications: the perfused plasma volume per 1 session is 0.5–1 CPV; no replacement fluid is required.

3.3. Surgical treatment of MG

Comment: surgical intervention is performed electively with preliminary stabilization of the condition in severe cases of MG by means of a course of plasmapheresis, intravenous administration of normal human immunoglobulins, or intensification of immunosuppressive therapy [94,175,179,180]. No reliable advantages of the extended transsternal method over less invasive surgical techniques have been identified, so the use of minimally invasive interventions (thoracoscopic or robot-assisted thymectomy) is advisable [180]. The treatment effect occurs within 1 year after the intervention, manifesting as a decrease in the required dose and duration of immunosuppressive therapy, as well as a reduction in the number of disease exacerbations. The best results are noted in patients under 65 years of age with a short duration of MG (up to 5 years) [27].

Thymectomy is also performed in seropositive JMG. It is definitely indicated for adolescent patients with a generalized form of myasthenia with bulbar disorders, moderate or severe course, as well as in the presence of a history of myasthenic crisis.

In the vast majority of cases (about 70%), thymectomy in early-onset myasthenia gravis leads to sustained long-term remission, and in some cases, complete discontinuation of all medications is possible. Special attention should be paid to young children; the probability of remission is highest in this population. Prior to thymectomy, maximal compensation of bulbar and respiratory disorders must also be achieved [18,181–185].

Comment: surgical intervention is performed electively with prior condition stabilization in severe MG cases using a course of plasmapheresis, intravenous normal human immunoglobulins, or intensification of immunosuppressive therapy [94,175,179,180]. If a thymoma is present, all thymic tissue is removed along with the tumor [94,179]. For thymomas, an extended transsternal approach may be advisable in the presence of invasive growth, pronounced adhesions, and the risk of massive bleeding that is difficult to control using minimally invasive techniques. In other cases, preference should be given to minimally invasive techniques (thoracoscopic and robot-assisted thymectomy) [186].

3.4. Management of MG in pregnancy

MG is not a hereditary disease, and therefore the family can have healthy children without restrictions. The only limitation may be the severity of MG itself, but under conditions of disease compensation, even this limitation is removed. Moreover, in many female patients with myasthenia gravis, remission develops during pregnancy, and they either do not need anticholinesterase drugs at all or take minimal doses. Some deterioration in condition is possible in the later stages of pregnancy. Extremely rarely, deterioration may occur requiring pregnancy termination. Significantly more complex is the early postpartum period, during which about 30% of women note a worsening of myasthenia symptoms.

Comment: parenteral administration of anticholinesterase agents should be avoided, especially in the third trimester, due to the risk of preterm labor [190].

Comment: #Prednisolone** as a pathogenetic therapy for myasthenia gravis during pregnancy is considered safe, but should be used at the lowest effective doses. Doses exceeding 20 mg orally per day of #prednisolone** should be avoided in pregnant and lactating women [205]. Safety data are based on registry studies involving a large number of pregnant women, as well as long-term clinical observations. A large study based on the Danish registry did not reveal an increased risk of malformations, including cleft palate, which was identified in older studies [194,195]. A retrospective study conducted in Australia also showed no increased risk of cleft palate or neural tube defects in the fetus, although this study observed an increased risk of congenital urogenital tract anomalies in women who underwent in vitro fertilization [196]. #Prednisolone** is preferred because it is metabolized by the placenta and only 10% reaches the fetal bloodstream [197–201]. It must be taken into account that the use of high doses of GCs increases the risk of gestational diabetes and arterial hypertension in the mother. Also, the intake of high doses of GCs during pregnancy may be associated with intrauterine growth restriction, preterm birth, and premature rupture of membranes [195,202–204].

Comment: animal studies have revealed a teratogenic effect of #azathioprine** when administered at doses comparable to human therapeutic doses. However, clinical data have not confirmed a teratogenic effect in humans. #Azathioprine** is considered safe during pregnancy [208,209].

Comment: if pregnancy is not planned, effective methods of contraception should be used to minimize the likelihood of fetal exposure to potentially harmful medications in the event of an unplanned pregnancy [201,211]. 

Comment: #Mycophenolate mofetil** should be discontinued at least 6 weeks before conception. #Methotrexate** and cyclophosphamide** should be discontinued at least 3 months prior to planned pregnancy [212–215].

Comment: magnesium sulfate** is contraindicated in female patients with myasthenia gravis during preeclampsia/eclampsia as it may precipitate a myasthenic crisis. If an eclamptic seizure occurs, appropriate antiepileptic drugs (N03) can be used instead of magnesium sulfate** [216,217].

3.5. Anesthesia in MG

General anesthesia is not contraindicated in patients with MG in remission when surgery is required. When planning anesthesia and surgical intervention, preliminary stabilization of the patient's condition and compensation of myasthenic symptoms through disease-modifying therapy are required to prevent the progression of generalized muscle weakness and the need for prolonged postoperative ventilatory support. A thorough preoperative evaluation of the patient with MG is necessary, including mandatory clinical assessment by multidisciplinary specialists (anesthesiologist-resuscitologist, surgeon, cardiologist, pulmonologist, neurologist) and respiratory function testing [218–222]. Oral anticholinesterase agents, if necessary, should be continued throughout the preoperative period, except for the morning of surgery, as they may interact with muscle relaxants and increase bronchial secretions [218,221,222]. 

Comment: the use of sedatives (diazepam**) and opioids can depress respiratory function in patients with MG. If opioids are required, they should be prescribed with extreme caution. In patients older than 1 year, remifentanil and fentanyl** are preferred. Drugs should be prescribed at the lowest possible dose and carefully titrated [218,223,224].

Comment: cautious use of short-acting nondepolarizing muscle relaxants is possible (in patients older than 1 month - rocuronium bromide**). The standard recommended initial dose of rocuronium bromide** for patients of any age is 0.6 mg/kg, the maintenance dose for patients over 18 years is 0.1–0.2 mg/kg, and for children it is 0.075–0.125 mg/kg [186, 225]. Sugammadex** can be used to reverse neuromuscular blockade induced by rocuronium bromide** or vecuronium bromide, and in children and adolescents aged 2 to 17 years to reverse neuromuscular blockade induced by rocuronium bromide**. Its use has been shown to be associated with a lower risk of myasthenic crisis after thymectomy [226–228].

Comment: anesthesia with propofol** and sevoflurane** without muscle relaxants in patients with MG provides safe and effective conditions for thoracoscopic thymectomy. Sevoflurane** provides a higher level of intraoperative muscle relaxation than propofol** [229–232]. Sodium oxybate** should be avoided [218, 223, 224].

Comment: performing local or regional anesthesia makes it possible to avoid the use of general anesthesia, opioids, hypnotics, and sedatives in the intraoperative period, and to manage pain syndromes in the postoperative period. If necessary, epidural and spinal anesthesia can also be used. The use of amide local anesthetics (bupivacaine**, mepivacaine (in children older than 4 years, body weight over 20 kg), ropivacaine**, lidocaine**) is indicated. Local anesthetics of the aminobenzoic acid ester group (procaine**) should be avoided [233–235].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: moderate physical activity does not cause adverse effects and is indicated for patients with mild and moderate forms of the disease (MGFA IIA and IIB) [236].

5. Prevention and Dispensary Observation

Comment: it is important to apply comprehensive treatment of comorbidities that increase the risk of infections and strictly follow vaccination protocols.

6. Organization of Medical Care

Indications for hospital admission:

Elective hospitalization

1) Administration of normal human immunoglobulins, eculizumab**, ravulizumab, #rituximab**, as well as plasmapheresis is carried out in a hospital setting.

2) Initiation of GCS therapy in patients with severe myasthenia gravis with bulbar and respiratory disorders due to a possible initial worsening of the condition during GCS therapy.

Emergency hospitalization

1) Presence of progressive bulbar and respiratory disorders posing a potential threat of crisis development.

2) Myasthenic crisis.

Indications for discharge of a patient from a medical organization

Stabilization of the patient's condition with sustained recovery of respiratory function and bulbar disorders.

7. Additional Information

Early-onset myasthenia gravis is 3 times more common in women than in men, and this category includes women of childbearing potential [239]. Before starting therapy in patients of this age, reproductive plans should be clarified. Choosing the appropriate treatment option requires balancing the risk of fetal effects against the risk of worsening. Counseling on family planning for women of childbearing age is advisable. Thymectomy should be considered for women of childbearing age before pregnancy, as this may reduce the risk of worsening myasthenic symptoms during pregnancy and the occurrence of transient neonatal myasthenia gravis [240, 241].

Most myasthenic crises are due to specific causes, among which respiratory infections are the most common [242]. Precipitating factors may also include surgery, pregnancy, non-compliance with therapy regimens, medications that worsen the course of myasthenia gravis, vaccinations, and emotional stress. However, in 30–40% of patients, a specific triggering factor cannot be identified [243]. As a result of a precipitating factor, a significant deterioration in neuromuscular transmission develops, caused by an autoimmune process leading to a critical deficiency of acetylcholine in the synaptic cleft. The number of comorbidities, the need for intubation, prolonged mechanical ventilation, and an infection-triggered myasthenic crisis are associated with an unfavorable outcome [237, 238].

Correct diagnosis, timely and adequate treatment lead to disease remission in more than 80% of patients with myasthenia gravis.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Tatiana M. Alekseeva, MD, PhD, Professor, Head of the Department of Neurology with a Clinic, Institute of Medical Education, Almazov National Medical Research Centre of the Russian Ministry of Health.

2. Yan V. Vlasov, Neurologist, Associate Professor, MD, PhD, President of the All-Russian Public Organization of Disabled Persons with Multiple Sclerosis, Professor at the Department of Neurology and Neurosurgery, Samara State Medical University of the Ministry of Health of the Russian Federation.

3. Alla B. Gekht, Corresponding Member of the Russian Academy of Sciences, MD, PhD, Director of the Z.P. Solovyov Scientific and Practical Psychoneurological Center of the Moscow Healthcare Department, Professor at the Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Academic Secretary of the All-Russian Society of Neurologists, Member of the Presidium of the National Stroke Association.

4. Olga V. Gilvanova, Functional Diagnostics Physician, Neurologist, Head of the Center for Neuromuscular Pathology, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department. Member of the All-Russian Society of Neurologists. Member of the Association of Clinical Neurophysiology Specialists (ASKLIN).

5. Evgeny I. Gusev, Academician of the Russian Academy of Sciences, Professor, MD, PhD, Professor at the Department of Neurology, Neurosurgery and Medical Genetics, Faculty of General Medicine, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, President of the National Stroke Association, President of the All-Russian Society of Neurologists.

6. Daniil A. Degterev, PhD in Medicine, Head of the Neurology Department, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department. Member of the Association of Clinical Neurophysiology Specialists (ASKLIN).

7. Sergey I. Dedayev, PhD in Medicine, Head of the Department for the Study of Pain and Somatoform Disorders, Z.P. Solovyov Scientific and Practical Center of the Moscow Healthcare Department. Member of the All-Russian Society of Neurologists.

8. Evgenia S. Druzhinina, PhD in Medicine, Associate Professor at the L.O. Badalyan Department of Neurology, Neurosurgery and Medical Genetics, Faculty of Pediatrics, Pirogov Russian National Research Medical University. Member of the All-Russian Society of Neurologists. Member of the Association of Clinical Neurophysiology Specialists (ASKLIN).

9. Dmitry S. Druzhinint, MD, PhD, Associate Professor at the Department of Nervous Diseases with a Course of Medical Genetics and Neurosurgery, Yaroslavl State Medical University of the Russian Ministry of Health. Member of the All-Russian Society of Neurologists. Chairman of the Association of Clinical Neurophysiology Specialists (ASKLIN).

10. Galina E. Ivanova, MD, PhD, Professor, Chief freelance specialist in medical rehabilitation of the Ministry of Health of the Russian Federation, Head of the Department of Medical Rehabilitation, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation. Chairman of the Union of Rehabilitologists of Russia. Chief freelance specialist in medical rehabilitation of the Russian Ministry of Health.

11. Patimat Sh. Isabekova, Neurologist at the Perinatal Center, Almazov National Medical Research Centre of the Russian Ministry of Health.

12. Lyubov F. Kasatkina, Doctor of Biological Sciences, Specialist in Functional Diagnostics of Peripheral Nervous System Diseases, Research Center of Neurology.

13. Maria O. Kovalchuk, Neurologist, PhD in Medicine, Head of Neurological Department No. 1, V.M. Buyanov City Clinical Hospital.

14. Andrey S. Kozlovsky, Neurologist, PhD in Medicine, Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

15. Sergey V. Kotov, Neurologist, MD, PhD, Professor, Chief Researcher of the Neurological Department, Head of the Department of Neurology, Faculty of Advanced Medical Training, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky.

16. Elizaveta S. Makashova, Neurologist, N.N. Burdenko National Medical Research Center of Neurosurgery of the Ministry of Health of the Russian Federation, Center for Neuromuscular Pathology, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department.

17. Nadezhda A. Malkova, Neurologist, MD, PhD, Professor at the Department of Clinical Neurology and Neurogeriatrics, Novosibirsk State Medical University of the Russian Ministry of Health, Head of the Regional Center for Multiple Sclerosis and Other Autoimmune Diseases of the Nervous System, State Novosibirsk Regional Clinical Hospital.

18. Mikhail Yu. Martynov, Corresponding Member of the Russian Academy of Sciences, Professor, MD, PhD, First Deputy General Director of the Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency, Acting Head of the Department of Neurology, Neurosurgery and Medical Genetics, Faculty of General Medicine, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Scientific Secretary of the All-Russian Society of Neurologists, Board Member of the National Stroke Association.

19. Evgenia A. Melnik, PhD in Medicine, Leading Researcher, Scientific and Advisory Department, Research Centre for Medical Genetics, Associate Professor at the Department of Genetics of Neurological Diseases, Institute of Higher and Additional Professional Education, Research Centre for Medical Genetics.

20. Alexander G. Sanadze, Neurologist, MD, PhD, Professor, Head of the Outpatient Clinic for Myasthenia Gravis Patients, V.M. Buyanov City Clinical Hospital of the Moscow Healthcare Department, Member of the All-Russian Society of Neurologists.

21. Elena K. Sepp, Neurologist, PhD in Medicine, Neurologist at the NMK Neuromuscular Diseases Clinic.

22. Dmitry V. Sidnev, Neurologist, MD, PhD, Head of the Outpatient Clinic for Myasthenia Gravis Patients, V.M. Buyanov City Clinical Hospital of the Moscow Healthcare Department, Member of the All-Russian Society of Neurologists.

23. Olga P. Sidorova, MD, PhD, Professor at the Department of Neurology, Faculty of Advanced Medical Training, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky.

24. Mikhail V. Sinkin, Neurologist, Functional Diagnostics Physician, MD, PhD, Leading Researcher, Sklifosovsky Research Institute for Emergency Medicine of the Moscow Healthcare Department, Member of the Association of Clinical Neurophysiology Specialists (ASKLIN).

25. Ivan K. Ternovykh, Assistant at the Department of Neurology with a Clinic, Institute of Medical Education, Almazov National Medical Research Centre of the Russian Ministry of Health, Neurologist, Junior Researcher at the Research Laboratory of Neurology and Neurorehabilitation, A.L. Polenov Russian Neurosurgical Institute (a branch of the Almazov National Medical Research Centre of the Russian Ministry of Health).

26. Dmitry A. Tumurov, Neurologist, PhD in Medicine, Leading Researcher at the Department for the Study of Pain and Somatoform Disorders, Z.P. Solovyov Scientific and Practical Center of the Moscow Healthcare Department, Neurologist at the Outpatient Clinic for Myasthenia Gravis Patients, V.M. Buyanov City Clinical Hospital of the Moscow Healthcare Department, Member of the All-Russian Society of Neurologists.

27. Nikolay A. Shamalov, MD, PhD, Professor, Chief Freelance Neurologist of the Ministry of Health of the Russian Federation, Chief Freelance Neurologist of the Moscow Healthcare Department, Director of the Institute of Cerebrovascular Pathology and Stroke, Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency, Executive Secretary of the National Stroke Association.

Conflict of interest:

The members of the working group declared no financial or non-financial conflicts of interest regarding the topic of these clinical guidelines. Working group member(s) who reported circumstances that could potentially lead to a conflict of interest were excluded from the discussion of sections related to the conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Neurologists, general practitioners, pediatricians, family physicians;

2. Medical students, residents, postgraduate students;

3. Faculty members, researchers.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2.  Scale for assessing levels of evidence (LoE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for grading grades of recommendation (GoR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

List of drugs contraindicated in myasthenia gravis

Narayanaswami P. et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020  Update. // Neurology. UnitedStates, 2021. Vol. 96, № 3. P. 114–122;

Myasthenia Gravis and Myasthenic Syndromes / Sanadze A.G. - Moscow : GEOTAR-Media, 2019. - 256 p.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

1. What is myasthenia gravis?

Myasthenia gravis is an autoimmune disease characterized by impaired signal transmission from nerves to muscles. This leads to muscle weakness that increases with exertion and improves at rest.

2. Main symptoms

• Eyes: drooping of the eyelids (ptosis), double vision (diplopia).

• Face and throat: difficulty chewing, swallowing, slurred speech.

• Limbs: weakness in the arms/legs, rapid fatigue.

• Respiration: shortness of breath, weakness of the respiratory muscles (requires emergency care!).

3. What to do in case of clinical deterioration?

• Myasthenic crisis (severe weakness, respiratory/swallowing impairment):

  • Call an ambulance immediately (103/112)!

  • Inform the physician about the diagnosis of "myasthenia gravis".

• Scheduled medical consultation: in case of increasing weakness, infections, or altered response to medications.

4. Treatment: key rules

• Medications:

  • #Pyridostigmine bromide** — improves neuromuscular transmission (take strictly on schedule!).

  • Corticosteroids and immunosuppressants — reduce the activity of the immune system.

  • Monoclonal antibodies — in severe cases.

• Non-pharmacological methods: plasmapheresis, thymectomy (removal of the thymus gland).

• Important:

  • Do not miss medication doses!

  • Avoid self-treatment — many medications are dangerous in myasthenia gravis (see Section 5).

5. Hazardous factors and contraindications

• Avoid:

  • Stress, sleep deprivation, physical exhaustion.

  • Infections — maintain hygiene, get vaccinated (only after consulting a physician!).

  • Medicines:

    • Systemic antibacterials (aminoglycosides, fluoroquinolones).

    • Muscle relaxants, magnesium preparations, beta-blockers.

    • Hypnotics and sedatives without medical consultation.

  • Overheating (saunas, hot baths).

6. Lifestyle: Recommendations

• Daily routine: alternate activity and rest. Avoid prolonged strain on a single muscle group.

• Nutrition:

  • Eat soft foods if swallowing is impaired.

  • Take #pyridostigmine** bromide 30–40 minutes before meals to improve chewing.

• Physical activity:

  • Moderate exercise (walking, swimming, yoga) after consulting a doctor.

• Home safety:

  • Install grab bars in the bathroom, avoid slippery surfaces.

7. Pregnancy and Myasthenia Gravis

• Plan pregnancy during a period of remission.

• Be regularly monitored by a neurologist and an obstetrician-gynecologist.

• Certain medications (e.g., #azathioprine**) may be safe, but require monitoring.

8. Contacts

• Attending neurologist: _______________________

• Emergency phone number: 103/112.

• Emergency relative contact: _______________

Important!

• Always carry a medical ID/bracelet indicating your diagnosis.

• Undergo an annual examination as agreed with your attending physician.

Check yourself:

• Do you know the symptoms of a myasthenic crisis?

• Do you always carry your list of medications with you?

• Have you discussed an action plan for infections/stress with your doctor?

This leaflet does not replace a medical consultation. Check individual recommendations with a specialist.

Reliability verified by:

• MGFA (Myasthenia Gravis Foundation of America) guidelines.

• Sanadze A.G. methodical manual "How to Live with Myasthenia Gravis".

• Current clinical treatment protocols (2020–2023).

If you find inaccuracies or need additions, please contact your attending physician.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Medical Research Council Scale for Muscle Strength Assessment

Russian title: Medical Research Council Scale for muscle strength.

Original title: The Medical Research Council Manual Muscle Testing (MRC).

Source: Kleyweg RP, van der Meché FG, Schmitz PI. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve. 1991 Nov;14(11):1103-9. doi: 10.1002/mus.880141111. PMID: 1745285.

https://www.ukri.org/councils/mrc/facilities-and-resources/find-an-mrc-facility-or-resource/mrc-muscle-scale/

Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

Purpose: for quantitative assessment of muscle strength.

Content:

Note: indicate the MRC score for each muscle in whole numbers.

Key (interpretation): scoring of the strength of the tested muscles is carried out according to the data given in the table.

Explanations: testing of all muscles is based on the principles of manual muscle testing. The specialist should know the position of the tested body part and which movement allows the tested muscle to be loaded to the greatest extent. The specialist ensures that agonist muscles are, as far as possible, "excluded" from the movement, and the tested muscle is maximally "engaged" in the work.