Myasthenia Gravis

Myasthenia gravis is a chronic autoimmune disease in which muscle tone decreases. The exact causes of the onset of pathology have not yet been determined. Thymus hyperplasia, oncology, and systemic connective tissue diseases can provoke the development of MG. Asthenic bulbar palsy can be congenital or acquired.

Myasthenia gravis most often develops in women between the ages of 20 and 40 and men between 50 and 80 but can occur at any age.

MG develops as a result of an autoimmune attack on postsynaptic acetylcholine receptors, as a result of which neuromuscular transmission is disrupted. The cause of autoantibody formation is unknown, but the disease has been associated with thymic abnormalities, autoimmune thyroiditis, and other autoimmune disorders (e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pernicious anemia).

The role of the thymus in MG is unclear, but 65% of patients have thymic hyperplasia, and 10% have thymoma. About half of thymic tumors are malignant.

Precipitating factors for myasthenia gravis include:

• Infection;
• Surgery;
• Certain medicines (e.g., aminoglycosides, quinine, magnesium sulfate, procainamide, calcium channel blockers, immune checkpoint inhibitors).

Ocular MG is characterized by damage to the outer muscles of the eye. It occurs in 15% of patients.

Congenital myasthenia gravis is a rare autosomal recessive disorder with onset in childhood. This disease is not immune-mediated and is caused by presynaptic or postsynaptic abnormalities.

Ophthalmoplegia is common in patients with congenital MG.

Myasthenia gravis occurs in 12% of children whose mothers suffer from this disease. It is connected with immunoglobulins of the IgG class, which passively cross the placenta; this leads to general muscle weakness developing, which disappears over a few days or weeks as the antibody titer decreases. These patients require supportive care.

Symptoms and Causes of Myasthenia Gravis

Symptoms

Myasthenia gravis is a chronic, constantly progressive disease. Initially, it affects the muscle tissues of the face, then spreads to the trunk. The following types of MG are distinguished:

1. Ocular – the nerve endings in the cranial region are affected, and the eyelids fall asymmetrically. The patient complains of double vision and deterioration in visual acuity. Gradually focusing on one subject becomes difficult.
2. Bulbar – the lesion extends to the masticatory muscles and tissues of the larynx. The patient’s voice changes, speech becomes quieter and nasal. Some consonants are very difficult to pronounce, and stuttering develops. Due to the penetration of fluid into the respiratory tract, the risk of pneumonia increases.
3. Lambert-Eaton – the muscles of the arms, legs, and neck do not receive nerve impulses. It is difficult for the patient to coordinate these areas of the body. This form is diagnosed in the elderly and is characterized by rapid progression.
4. Generalized – the muscles of the eyes are immediately affected, then the process spreads to the larynx, arms, legs, and hips. The main danger of this form is that the respiratory muscles are affected over time.

The disease is characterized by constant progression. The patient may experience both the constant presence of disturbances and short-term episodes. The symptoms of MG can be recognized by variable muscle weakness, rapid fatigue, voice changes, gait, and shortness of breath.

Causes

MG is congenital and acquired. The first is associated with a gene mutation responsible for the formation of synapses – adapters through which a nerve impulse travels. As a result, the tissue cannot receive the task from the brain. The following factors can provoke the development of acquired MG:

• neoplasms – benign and malignant;
• other autoimmune diseases;
• excessive physical activity;
• consequences of viral and bacterial infections;
• postponed injuries;
• long-term medication;
• hormonal disorders;
• frequent stress, anxiety.

The following factors can contribute to the development of myasthenia gravis:

• diseases of the central nervous system, hyperplasia;
• thyrotoxicosis;
• scleroderma;
• encephalitis;
• frequent colds;
• systemic diseases;
• genetic predisposition;
• taking alcohol and drugs.

Diagnostics of Myasthenia Gravis

Diagnostics consists of the following stages:

• patient’s medical treatment;
• determination of the level of antibodies of the acetylcholine receptor, electromyography, or both.

Symptoms and signs of the disease, confirmed by test results, can be suspected of a diagnosis of myasthenia gravis.

Bedside Testing

The traditional bedside test using the short-acting (<5 minutes) drug edrophonium is not used in the United States and many other countries.

Since muscle weakness in MG decreases with a decrease in temperature, an ice test can be performed in patients with ptosis. 

1. An ice pack is applied to the patient’s closed eye for 2 minutes. The test result is positive if the ptosis is completely or partially resolved. The ice test is usually not useful in patients with ophthalmoparesis.
2. Patients with ophthalmic paresis can be evaluated with relaxation tests. For this test, patients are asked to lie quietly in a dark room for 5 minutes with their eyes closed. The test result is considered positive if, after resting, paresis of the oculomotor muscles is resolved.

Antibody Detection and Electromyography

If one of the bedside tests is positive, several of these items are needed to confirm the diagnosis:

• Determination of serum levels of antibodies to acetylcholine receptors;
• Electromyography (EMG).

With EMG using repetitive stimuli (2-3 per second), 60% of patients show a decrease in the amplitude of the electrically evoked muscle response by more than 10%. Single fiber EMG reveals neuromuscular conduction disorders in more than 95% of patients.

Further Research

1. After the diagnosis of myasthenia gravis, CT or MRI of the chest organs should be performed to look for thymic hyperplasia and thymoma.
2. Screening tests for autoimmune diseases that often accompany MG (e.g., pernicious anemia, autoimmune thyroiditis, rheumatoid arthritis, systemic lupus erythematosus) should be performed.
3. Patients with a myasthenic crisis should receive an evaluation for the presence of an infectious trigger.
4. Lung function assessments (such as forced vital capacity) help assess the risk of developing respiratory failure.

Etiology

Muscle weakness with MG develops due to damage to the postsynaptic membrane of the neuromuscular junction (the place where the nerve ending connects to myocytes). In this place, under the action of an electrical impulse, acetylcholine is released from the presynaptic membrane of the nerve ending.

1. Acetylcholine attaches to its receptors on the surface of the muscle cell. 
2. As a result, ion channels open, and the concentration of sodium in the muscle cell increases, which leads to membrane depolarization, causing muscle contraction.
3. With MG, antibodies to acetylcholine receptors are formed on the postsynaptic membrane, and the transmission of impulses through the muscle cell is blocked.
4. Residual tissues of the thymus play an important role in the disease’s development, which stimulates the body’s immune system to attack its tissues. 
5. Thymus hyperplasia is observed in 65% of patients with MG and 15% thymoma. 
6. Half of the patients with thymoma subsequently develop myasthenia gravis.

Myasthenia Gravis Treatment

This disesease can’t be cured. But it can be treated with medications and in some cases with surgery. 

1. Anticholinesterase medications to relieve symptoms

To reduce the autoimmune response, use corticosteroids, immunomodulatory therapy (intravenous immunoglobulin, plasmapheresis), immunosuppressants, or thymectomy;

2. Supportive therapy

In patients with congenital myasthenia gravis, anticholinesterase drugs and immunomodulatory treatments are ineffective and should not be used. Patients with respiratory failure should be intubated and transferred to mechanical ventilation.

3. Symptomatic treatment

Anticholinesterase drugs form the basis of symptomatic treatment, but they do not affect the pathological process. They rarely eliminate all symptoms, and the disease may become refractory to their use.

• pyridostigmine treatment starts with 60 mg orally every 3-4 hours and increases to a maximum dose of 120 mg based on symptoms;
• if parenteral administration is necessary (for example, due to dysphagia), neostigmine can be used (1 mg corresponds to 60 mg of pyridostigmine);
• anticholinesterase drugs can cause abdominal cramps and diarrhea, which are treated with atropine 0.4 to 0.6 mg orally (given with pyridostigmine or neostigmine) or propantheline 15 mg 3-4 times a day.

Patients who have responded well to treatment and then become worse require respiratory support because they may have a cholinergic crisis, and the use of anticholinesterase drugs should be discontinued for several days.

4. Immunomodulatory treatment

Immunosuppressants suppress the autoimmune response and slow the course of myasthenia gravis disease but do not lead to a rapid decrease in the severity of symptoms. 

• Intravenous immunoglobulins at a dose of 400 mg/kg once a day for 5 days cause improvement in 70% of patients after 1-2 weeks. The effect can last from 1 to 2 months. 
• Plasmapheresis (for example, 5 sessions with the removal of 3-5 liters of plasma for 7-14 days) has a similar effect.
• In maintenance therapy, glucocorticoids are necessary; but in myasthenic crises, they do not have an immediate effect. In more than half of cases, after starting treatment with high-dose glucocorticoids, a sharp deterioration occurs. Treatment begins with prednisolone 10 mg orally once a day; each week, the dose is increased by 10 mg up to 60 mg, and the patient takes it for about 2 months, followed by a chalky decrease. Improvement occurs in a few months; then, the dose must be reduced to the required minimum to ensure symptom control.
• Azathioprine 2.5–3.5 mg/kg once daily may be as effective as glucocorticoids, although there may be no improvement for many months. By taking cyclosporine 2.0–2.5 mg/kg orally 2 times a day, you can reduce the dose of glucocorticoids. These drugs require special care.
• Other effective drugs include methotrexate, cyclophosphamide, and mycophenolate mofetil. In patients with resistant disease, monoclonal antibodies (rituximab, eculizumab) may be effective, but they are expensive.
• Thymectomy may be indicated in patients with generalized myasthenia gravis if they are <80 years of age. Subsequently, in 80% of cases, remission occurs, or the amount of maintenance therapy can be reduced.

Before thymectomy for myasthenic crises and in resistant patients, plasmapheresis or intravenous immunoglobulins are effective.

FAQs

• How many years do people live with a diagnosis of myasthenia gravis?

Patients can live until old age, subject to the doctor’s recommendations and regular examination. On average, myasthenia gravis appears at the age of 20-40, more often in women. After its manifestation, it is important to start treatment immediately and adhere to it until the patient gets better.

• How serious is myasthenia gravis?

 Only the eye muscles are hit about 1 in 5 people. Therapy can help keep the symptoms under control. Very rarely, MG can resolve or get better on its own. If not treated in time, MG can be a threat to life, but it does not have a major influence on lifespan for most people.

• Is exercise good for myasthenia gravis?

Physical training and exercise are safe in patients with MG; physical training programs reduce variable muscle weakness and daily functioning in patients with this disease. Respiratory muscle function improves with endurance training in patients with MG.

• How to take prednisone in myasthenia gravis?

The dose of prednisone is based on an individual assessment of the severity of the patient’s condition. On average, the dosage is determined at the rate of 1 mg per 1 kg of body weight, but should not be less than 50 mg.

• What diseases are similar to myasthenia gravis?

Many disorders may mimic MG, including generalized fatigue, amyotrophic lateral sclerosis (ALS), Lambert-Eaton myasthenic syndrome, botulism, penicillamine-induced myasthenia, and congenital myasthenic syndromes.

• What should not be consumed in the presence of myasthenia gravis?

It is categorically contraindicated:

1. Diuretics (lasix, furosemide), with the exception of veroshpiron; 
2. сurariform muscle relaxants, GHB, antipsychotics, and tranquilizers; 
3. sedative (sedative) drugs (except for Grandaxin, Adaptol, bromine, motherwort, valerian, Corvalol, valocordin).