Myasthenia gravis

Content

Introduction

Myasthenia gravis (MG) is a rare disease caused by an abnormal (autoimmune) immune response that impairs the communication between nerves and muscles, causing fatigue and muscle weakness (the term myasthenia, of Greek origin, means muscle without strength). It manifests itself in a variable way and, generally, has a progressive (chronic) course over time.

MG is an autoimmune disease, which means that the body's defense system (immune system) mistakenly attacks certain parts of the body because it does not recognize them as its own. In MG the body produces antibodies that prevent a molecule, the " acetylcholine, to transmit impulses from the nerve to the muscle. MG is therefore a disease that affects the neuromuscular junction, the muscle of the person with MG is healthy but is weakened, as the impulse for muscle contraction does not pass or is insufficient.

Generally, MG manifests with visual disturbances, described primarily as doubling of the image, and with the drooping of one or both eyelids. Other frequent symptoms are difficulty chewing and swallowing. Some patients develop generalized muscle weakness. Muscle weakness fluctuates, worsens with activity and improves with rest.

MG affects both genders; it can appear at any age, from children to the elderly, but occurs more frequently between 20 and 40 years in females (early onset form), and over 50 years in males (late onset form).

There is still no definitive cure for MG but several therapies help to keep the disorders (symptoms) under control.

Symptoms

Myasthenia gravis (MG) is characterized by weakness and fatigue of the voluntary muscles, or muscles of the human body that contract when a person wants it. The severity of muscle weakness differs from person to person, ranging from mild and limited deficits to single muscle groups to generalized weakness. The main disorder (symptom) is exhaustion; muscle weakness worsens with activity and in the evening and improves after periods of rest. The course of the disease is extremely variable; it can be characterized by long periods during which disturbances diminish or disappear, or progress rapidly.

The involvement of the ocular muscles is very frequent and manifests itself with the lowering of one eyelid, or alternatively the lids of the two eyes (palpebral ptosis), and with a double vision of the image (diplopia). Oculomotor disorders are present in 70-80% of patients with MG. In about 15% of patients, the disease affects only the eye muscles (ocular myasthenia), but in the majority of cases, usually within the first two years after the first symptoms appear, the muscle weakness extends to muscles in other parts of the body (myasthenia generalized).

The involvement of the muscles of the face (mimic muscles) causes difficulties in closing the eyes and a general reduction in the expressiveness of the face. When the chewing, pharynx and tongue muscles are involved, there are difficulties in chewing, swallowing and speaking ( the voice may become “nasal”.) The involvement of the muscles of the neck, trunk and limbs can cause difficulty in keeping the head erect, keeping the arms raised, climbing stairs or walking for a long time.Impaired chest muscles can cause breathing difficulties, especially when lying down or after exercise.

Sudden (acute) episodes, called myasthenic crises, may occur in some people, characterized by a rapid worsening of difficulty in breathing and, sometimes, in swallowing, with weakness in the limbs. Respiratory failure requiring assisted ventilation is a serious event requiring immediate transfer of the patient to the ICU. Such crises can be caused by infections, surgery, or contraindicated drugs in myasthenia.

Causes

As with other autoimmune diseases, the cause of myasthenia gravis (MG) is not known. Although MG is not a hereditary disease, it is believed that genetic predisposition and environmental factors as yet not well defined interact to alter the body's defense system (immune system) and cause the production of autoantibodies. In MG, the autoantibodies are directed against two molecules that are expressed on the membrane of striated muscle cells (also called voluntary muscles): the acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK).

Anti-AChR antibodies are present in 85% of patients with generalized MG and in about 50% of cases of ocular myasthenia; they are particularly common in late-onset MG. These autoantibodies bind to acetylcholine receptors causing their destruction; the number of receptors on the muscle cell membrane is therefore decreased. Consequently, the neurotransmitter released by the motor nerve, acetylcholine, is no longer able to exert its action, that is, to regulate the contraction of the muscles. MG with anti-AChR antibodies is often associated with changes in the thymus, such as enlargement (hyperplasia) and thymoma, a tumor of the thymic epithelial cells, almost always benign.The thymus is a gland located between the two lungs and has the task of 'instructing' the immune system not to attack the body's cells. The enlargement of the thymus (thymic hyperplasia) is generally associated with the form with a juvenile onset, more frequent in women. Thymoma is present in 15-20% of patients, especially between 40 and 60 years of age. Alterations that induce the production of anti-AChR autoantibodies are thought to occur in the thymus.

In a minority of patients with MG (5-8%) antibodies are produced against a molecule called MuSK, which is important for the distribution and therefore the function of acetylcholine receptors on the muscle membrane. The blocking of MuSK function by autoantibodies causes a severe alteration of neuromuscular transmission. Unlike myasthenia with anti-AChR antibodies, ocular forms are rare in myasthenia with anti-MuSK antibodies, facial, oral-pharyngeal and respiratory muscles are most affected, limb deficits are generally mild or absent, and are not present. significant changes in the thymus.

More rarely, people with MG produce autoantibodies against two other molecules found on muscle cells, called LRP4 and agrin; these autoantibodies are often present in association with anti-AChR or anti-MuSK antibodies.

Diagnosis

The first disorders that can lead to suspicion of myasthenia gravis (MG) are fluctuating strength deficits and "muscle fatigue." The assessment (diagnosis) is based on the demonstration of a neuromuscular transmission disorder by means of electromyography and the detection of autoantibodies. Another element in favor of the detection of MG is the immediate response to a type of drugs, called anticholinesterases, which promote neuromuscular transmission.

Electromyography

It is an instrumental test that allows you to evaluate the response of the muscle to the stimulation of a motor nerve, and therefore to detect the blockage of neuromuscular transmission which in people with MG is due to the reduction of acetylcholine receptors on the muscle. The exam consists in inserting small needles connected to electrodes into the muscles to measure the transmission of the electrical impulse from the nerve to the muscle. Single-fiber electromyography allows you to evaluate the activation of individual muscle fibers innervated by the same nerve end; this investigation is useful for highlighting a defect in neuromuscular transmission in patients with mild or undetectable disorders.

Measurement of anti-AChR and anti-MuSK antibodies in the blood

It is a very specific test and a positive result in a patient with symptoms consistent with MG confirms the diagnosis. However, a negative test result does not rule out MG and it is advisable to repeat the assay. The amount of autoantibodies is not indicative of the severity of the disease but may vary with the clinical picture and response to therapy. The net reduction of complaints after drug administration is another factor in favor of the diagnosis of MG. Anticholinesterase drugs increase the availability of the neurotransmitter acetylcholine and thus improve neuromuscular transmission, allowing residual receptors on the muscle to be activated repeatedly. Currently, the drug test uses neostigmine intramuscularly; the response occurs in about 15-20 minutes and lasts for about an hour. Orally administered pyridostigmine may also be used for this test.

Radiological investigations

Once MG is ascertained, radiological tests such as computed tomography (CT) or nuclear magnetic resonance (MRI) of the chest are indicated to check if the thymus is enlarged or if there is a tumor (thymoma).Radiological examinations are also recommended as thymoma may occur, albeit rarely, in patients with antibodies other than anti-AChR or in patients without detectable autoantibodies (seronegative myasthenia). Thyroid hormones and anti-thyroid antibodies should also be measured, as MG is frequently associated with thyroid disease. A brain CT or MRI may also be done to rule out that the disturbances may be caused by a brain problem.

Therapy

Current treatments for myasthenia gravis (MG) can reduce complaints (symptoms) and improve patients' quality of life. MG therapy should be adapted as much as possible to the individual patient, taking into account various factors, such as the severity of the disorders, autoantibodies responsible for the disease, changes in the thymus, the age of the individual and the concomitance of other diseases (comorbidities).

Medicines

They include symptomatic drugs that aim to control disorders (symptoms) and immunosuppressive drugs that act on the immune system to reduce the autoimmune reactions underlying the disease.

Anticholinesterase drugs
Pyridostigmine is the most widely used drug as a first treatment for MG. Increases the levels of acetylcholine at the neuromuscular receptors, improving muscle contraction; it can reduce or eliminate ailments (symptoms) but does not act on the causes of the disease. Since the effect of the drug lasts 3-4 hours, it is necessary to take it several times a day. Pyridostigmine can cause undesirable effects (side effects), such as stomach and muscle cramps, diarrhea, increased salivation, increased bronchial secretions, general malaise, which usually disappear by reducing the dosage of the drug. Anticholinesterase drugs are not suitable for people with anti-MuSK antibodies, in whom side effects are particularly pronounced.

Immunosuppressive drugs
In the event that anticholinesterase drugs are not able to control the disorders it is necessary to resort to immunosuppressive drugs; these drugs reduce the activity of the immune system by preventing the production of antibodies and, consequently, also of the anti-AChR and anti-MUSK autoantibodies that are the basis of myasthenia gravis.

Steroids or cortisones, generally prednisone, are the immunosuppressive drugs used first for their rapidity of action and high efficacy; may cause transient worsening of symptoms in the first few weeks of treatment. Chronic administration of steroids can cause undesirable effects (side effects), such as weight gain, mood changes and increased risk of infections. If steroid therapy is not sufficient to reduce symptoms or has to be used in high doses for a long period, the use of immunosuppressive drugs such as azathioprine, mycophenolate mofetil, cyclosporine and cyclophosphamide is recommended. These drugs reduce the dosage of steroids and can replace prednisone in long-term therapy; they can induce serious side effects (effects collateral) as an increased risk of infections, and liver or kidney problems, to prevent which appropriate periodic checks are necessary.

Biological drugs
In case of non-response to immunosuppressive drugs or the need for high dosages of steroids and other immunosuppressants with serious side effects, the administration of so-called biological drugs has recently been considered. Numerous studies have shown an improvement in symptoms and quality of life of people with MG treated with rituximab, a monoclonal antibody that causes the rapid destruction of B lymphocytes, the cells that produce antibodies.The use of this drug requires careful evaluation both before and during treatment for the risk of infectious and haematological complications.

Plasma exchange

It is a procedure that allows you to remove harmful molecules, such as autoantibodies, from the part of the blood free of cells (plasma). Plasmapheresis rapidly reduces the concentration of autoantibodies responsible for MG and is typically used as an emergency therapy in worsening stages of the disease.

High-dose human immunoglobulins

An "alternative to plasmapheresis is the intravenous administration of high-dose immunoglobulins from donor blood. Immunoglobulins, also effective in other immune diseases, act on the immune system by inhibiting the production and effects of the autoantibodies responsible for MG. Plasmapheresis is high-dose immunoglobulins do not replace pharmacological immunosuppressive therapy; thanks to their rapid efficacy, these therapies are extremely useful in the most severe forms of MG and, in combination with high-dose prednisone, in the treatment of respiratory crises.

Surgery (removal of the thymus)

Removal of the thymus (thymectomy) is performed above all in people with MG associated with anti-AChR antibodies. Surgery is indicated in patients with thymoma; in cases where a thymoma is not found, the opportunity to remove the thymus should be evaluated based on the characteristics of each patient. Especially in cases with juvenile onset, thymectomy is a "useful therapeutic option to reduce the dosage of immunosuppressive drugs and improve symptoms. Generally, it is an intervention that is scheduled after good symptom control has been achieved with drug therapy."

Several drugs are known to interfere with neuromuscular transmission and should be avoided in people with MG, or used with caution under close medical supervision, as they can worsen the symptoms of the disease. Among the contraindicated drugs there are some classes of antibiotics, antimalarials, antirheumatics, antiarrhythmics and anxiolytics.

In Italy, MG is included in the list of rare diseases exempt from the cost of the ticket (Decree of the President of the Council of Ministers of 12 January 2017, Annex 7) with the code RFG101 within the group of congenital and dysimmune myasthenic syndromes.

For further information on MG (diagnosis and treatment centers, patient associations) you can contact the Rare Diseases Toll-Free Telephone (TVMR) 800.89.69.49. The number is active from Monday to Friday from 9:00 to 13:00.

At European level, MG is studied within the European Reference Network for Rare Neuromuscular Diseases (EURO-NMD). The aim of the Network is to harmonize and indicate best practices for the detection (diagnosis) and treatment of the disease, to improve the equity of care services in the Member States, to reduce the time needed to ascertain the disease, to offer specialized training and education, implement e-health services, develop guidelines for care, promote translational and clinical research, and share high quality data.

Bibliography

Narayanaswami P, Sanders DB, Wolfe G, Benatar M, Cea G, Evoli A, Gilhus NE, Illa I, Kuntz NL, Massey J, Melms A, Murai H, Nicolle M, Palace J, Richman D, Verschuuren J. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021 Jan 19; 96: 114-122

In-depth link

Italian Association of Myasthenia and Immunodegenerative Diseases (AIM) - Amici del Besta Onlus

Italian Association MIAstenia onlus

Ministry of Health.Diagnosis and treatment centers. Specialized centers for myasthenia gravis

Italian Union for the fight against dystrophic syndromes (UILDM). Myasthenia gravis

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