Generality
Myasthenia gravis is a chronic condition characterized by fatigue and weakness of some muscles. It is an autoimmune disease in which the normal transmission of contractile signals, sent from the nerve to the muscle, is compromised.
In pathogenesis, some autoantibodies block post-synaptic receptors in the neuromuscular junction and inhibit the excitatory effects of acetylcholine (neurotransmitter). By reducing the signal efficiency, the patient experiences weakness, especially when trying to repeatedly use the same muscle. The initial symptoms of the disease include lowering of the eyelids (ptosis), diplopia, difficulty in speaking (dysarthria) and swallowing (dysphagia). Over time, myasthenia gravis affects other muscle areas; the involvement of the thoracic muscles leads to serious consequences on respiratory mechanics and, in some cases, patients must resort to artificial respiration. The pathology is extremely debilitating and sometimes even fatal. Current therapies for myasthenia gravis are aimed at cushioning the response of the immune system, reducing blood levels of autoantibodies. Treatment may include acetylcholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy (surgical removal of the thymus).
In short: how neuromuscular transmission occurs
In a healthy neuromuscular junction, the signals generated by the nerves produce the release of acetylcholine (Ach). This neurotransmitter binds to receptors (AChR) of muscle cells (at the level of the motor plate), causing an influx of sodium ions, which indirectly cause muscle contraction.
Causes
Communication between nerves and muscles . Myasthenia gravis is an autoimmune disease. This means that it develops as a result of selective hyperactivity of the immune system, in which patients produce abnormal (Ab) antibodies, because they are directed against a particular target in their body.
Normally, the ABs are produced in the immune response against foreign agents such as bacteria or viruses. In myasthenia gravis, however, the immune system mistakenly attacks normal body tissue components. In particular, specific autoantibodies for acetylcholine receptors (AChR) are produced, which bind to them by inactivating them. The end result is a decrease in the number of free receptors expressed on the surface of muscle cells. The loss of these surface receptors makes the muscle less sensitive to neuronal stimulation. Consequently, the increase in autoantibody levels reduces the efficiency of the neuromuscular junction, so patients suffering from myasthenia gravis manifest a progressive weakening of muscle tone. Vigorous physical activity requires an increase in chemical messages (with fewer available receptor sites, motor neurons are unable to reach the potential threshold useful for conducting the signal). This helps explain why people with myasthenia gravis have a worsening of symptoms after physical exertion and feel better after resting. The exact cause of this abnormal immune response is not yet fully understood.
Timo . In some people with myasthenia gravis, the thymus appears to be involved, a gland located in the thorax, behind the sternum, which plays an important role in the development of the immune system in early childhood (it produces hormones necessary for the development and maintenance of normal immune defenses) . From puberty, the involution of the gland begins and the thymic cells, once functionally active, are replaced by fibrous connective tissue.
Some adult patients with myasthenia gravis have an abnormal enlargement of the thymus or a thymoma (cancer of the thymic gland). The relationship between the thymus and myasthenia gravis is not yet fully understood, but this gland is clearly associated with the production of antibodies against the acetylcholine receptor.
Other considerations . The disease must be distinguished from congenital myasthenic syndrome, which may present similar symptoms, but does not respond to immunosuppressive treatments.
Signs and symptoms
To learn more: Symptoms Myasthenia gravis
The hallmark of myasthenia gravis is the fatigability of voluntary muscles, which worsens with repeated or sustained use. During periods of activity, the muscles become progressively weaker, while they improve after a period of rest (the symptoms can be intermittent).
The muscles that control the movement of the eyes and eyelids, facial expressions, chewing and swallowing are particularly susceptible.
The onset of the disease can be sudden and often the symptoms are intermittent. The degree of muscle weakness varies greatly between patients. Sometimes, it can occur in localized form, for example limited to the eye muscles (ocular myasthenia); in other cases, it can manifest with severe and generalized symptoms, affecting many muscle groups, including those that control breathing and neck and limb movements.
Symptoms of myasthenia gravis, which vary in type and severity, may include:
- Ptosis (lowering of the eyelids): it can be asymmetrical or affect both eyes;
- Double vision (diplopia): sometimes it occurs only when the gaze is directed in a particular direction;
- Blurred vision: may be intermittent.
- Unsteady and undulating gait;
- Weakness in the arms, hands, fingers, legs and neck;
- Problems with mastication and difficulty swallowing (dysphagia), due to the involvement of the pharyngeal muscles;
- Change in facial expressions, for the involvement of facial muscles;
- Shortness of breath;
- Dysarthria (alteration of the word, often becomes nasal).
Ocular myasthenia
General symptoms
Pain is usually not a characteristic symptom of myasthenia gravis, but if the neck muscles are affected, patients may experience back pain due to the effort to keep their heads raised.
Myasthenic crisis
A myasthenic crisis occurs when the upper chest muscles are involved; this represents a medical emergency that requires hospitalization and immediate medical treatment. Severe myasthenia gravis can produce respiratory paralysis, necessitating assisted ventilation. Some of the factors that trigger the myasthenic crisis include physical or emotional stress, pregnancy, infections, fever and adverse drug reactions.
How the disease progresses
The progression of myasthenia gravis is very variable over time and can potentially affect all the muscles of the body. However, in many cases, the disease does NOT progress to its terminal stage. For example, some patients only experience eye problems. From the onset of the disease, periods of accentuation of symptoms to remissions alternate. Myasthenia gravis can occasionally resolve spontaneously, but in most cases it is a condition that persists throughout life. However, with modern treatments, the symptoms can be well controlled.
Associated conditions
Myasthenia gravis is associated with various diseases, including:
- Thyroid disorders, including Hashimoto's thyroiditis and Graves' disease;
- Type 1 diabetes mellitus;
- Rheumatoid arthritis;
- Systemic lupus erythematosus;
- Demyelinating diseases of the central nervous system (eg multiple sclerosis).
Diagnosis
The diagnosis of myasthenia gravis can be complex, as the symptoms can be difficult to distinguish from other neurological disorders. A thorough physical examination can reveal easy fatigability, with improvement of weakness after rest and worsening with repetition of the stress test.
Myasthenia gravis is diagnosed by a series of tests, including:
- Blood test . Blood tests can identify specific antibodies (Ab), including:
- Acetylcholine abanti-receptor;
- Ab against the muscle-specific kinase receptor (MuSK is a specific muscle tyrosine kinase, present in some patients without antibodies against AChR);
- Ab direct against calcium channels (to exclude the myasthenic syndrome of Lambert Eaton).
In most people with the disease, identification of these specific autoantibodies is sufficient to confirm the diagnosis. However, further investigations may be necessary.
- Electromyography (EMG) . The doctor inserts a very thin needle into a muscle to measure the electrical response to nerve stimulation. In the case of myasthenia gravis, the response to repeated stimulation is atypical.
- Evidence of edrophonium. Injection of edrophonium chloride (Tensilon) blocks the enzyme that breaks down acetylcholine at the level of the neuromuscular junction. In patients with myasthenia gravis, the drug may cause a sudden and temporary improvement in symptoms.
- Diagnostic imaging . A chest X-ray is commonly performed to rule out other conditions, such as Lambert-Eaton syndrome, often associated with small cell lung cancer. A computed tomography and an MRI are the best tests to identify a thymoma (thymus tumor).
Treatment
There is no specific treatment for myasthenia gravis, but a series of treatments allow the management of symptoms effectively.
Some of the treatment options include:
- Lifestyle changes : adequate rest and minimization of physical effort.
- Cholinesterase inhibitors : the treatment of choice for myasthenia gravis and the administration of a cholinesterase inhibitor (an enzyme that degrades acetylcholine). Pyridostigmine, in particular, intervenes by increasing the ability of acetylcholine to compete with autoantibodies for receptors present in the terminal motor plates of neuromuscular junctions. The drug can temporarily improve muscle strength. The effect usually fades within 3-4 hours, so it will be necessary to take the tablets at regular intervals during the day. Possible side effects of the treatment include allergies, interactions with other drugs and symptoms of overdose such as diarrhea, nausea and vomiting. Sometimes, some medication is prescribed to help reduce side effects.
- Corticosteroids : these drugs work by suppressing the activity of the immune system and reducing the production of antibodies against the acetylcholine receptor. Corticosteroids are suspected to stimulate the synthesis of more AChR in muscle cells. Despite the good results, corticosteroids can cause more side effects than other types of therapy.
- Immunosuppressive drugs: drugs such as azathioprine, methotrexate and ciclosporin inhibit the production of autoantibodies. This helps to reduce the symptoms of myasthenia gravis. Immunosuppressive drugs can cause several side effects.
- Plasmapheresis : the procedure reduces the amount of autoantibodies circulating in the body. During plasmapheresis, the plasma is separated from the blood and cleaned by the Abacus-acetylcholine receptor. The blood is then re-infused to the patient. The symptoms should improve in two days, but the effects last only a few weeks (the immune system continues to create autoantibodies). Therefore, plasmapheresis is often used for situations where symptoms need to be controlled quickly, such as to help resolve a myasthenic crisis, and are not adequate for long-term treatment.
- Intravenous immunoglobulins: short-term management strategy involving intravenous administration of immunoglobulins (purified antibodies obtained from the plasma of blood donors). This treatment is very expensive, but can be useful during a myasthenic crisis that compromises the ability to breathe or swallow.
- Surgical approach ( thymectomy ): following surgical removal of the thymus, the patient may report some improvement in symptoms. It is not clear how thymectomy induces remission of myasthenia gravis, but research shows that, after surgery, the level of anti-acetylcholine receptor antibodies is reduced. However, surgical removal of the thymus is not a suitable procedure for all patients.
For further information: Medicines for the treatment of Myasthenia gravis ยป
Prognosis
The prognosis of myasthenia gravis is significantly improved with the introduction of immunosuppressive therapy. The availability of these and other treatments has significantly reduced mortality, allowing patients almost normal living conditions. However, people with myasthenia gravis often have to follow the treatment regimen for an indefinite period, as the symptoms generally tend to recur when treatment is stopped.
