Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. It is characterized by muscle weakness and muscle fatigue. Autoantibodies are produced which are directed towards the nicotinic acetylcholine receptor, which is located in the muscle membrane in its junction with the nerve terminal. Normally, when the nerve stimulus arrives at the nerve terminal, acetylcholine is released and it binds with the receptor which is located in the muscle membrane, thus making the muscle contract. In the presence of the acetylcholine receptor antibodies, these bind with the muscle membrane, preventing the released acetylcholine to bind to the receptor and thus the muscle does not contract. The clinical manifestations of this process are, as stated earlier, muscle weakness and muscle fatigue.
Myasthenia gravis can occur at any age. It has 2 peaks in incidence, one in the 2nd and 3rd decades, being more frequent in women, and another in the 5th and 6th decades, being more frequent in men.
In patients with myasthenia gravis it has been found that the presence of a thymoma (benign tumor of the thymus gland which is located in the chest) is considered a factor in the development and severity of the disease. It is found in 10-15% of patients with myasthenia gravis and a thymic lymphoid hyperplasia is found in 50-70% of patients. Thymic hyperplasia is found more frequently in young patients.
Other autoimmune disorders have been found to coexist in patients with myasthenia gravis. Thyroid autoimmune disease is the most frequent (10%). Other less frequent (5%) are systemic lupus erythematosus, rheumatoid arthritis and pernicious anemia.
Clinical features
The most common finding is muscle weakness, which is more apparent with the normal activities of the individual or with exercise. With the repetition of daily normal movements the patients gets tired easily, and with rest, his strength comes back to normal. It is common for the patient to complain that his symptoms are worse later in the day and at night.
The most common symptoms are:
- drooping eyelids
- eye muscle weakness
- double vision
- speech problems (weakness in articulation)
- weakness of facial muscles
- difficulty swallowing
- weakness of muscles holding the head up
- weakness of repetitive movements
- weakness while walking
- in severe cases muscles of respiration are affected
Myasthenia gravis is a disease which presents with exacerbations and remissions. Myasthenic crisis (worsening of the symptoms) can be produced by infections, surgery, medication interactions and stress.
Myasthenia gravis is classified as generalized and ocular (focal). Patients with the generalized form have all the above mentioned manifestations, whereas patients with the ocular form have a presentation with ptosis (droopy eyelid) and/or diplopia (double vision). Around 80% of patients with the ocular form may progress into the generalized form in 1-2 years.
Investigations
Upon clinical suspicion of myasthenia gravis, usually antibody testing is obtained. The most frequent presentation is with the presence of positive acetylcholine receptor antibodies. Approximately 85% of generalized myasthenia gravis and 50% of ocular myasthenia gravis will have positive antibodies against the acetylcholine receptor.
Other antibodies have been detected in this disease. One of these is MuSK (muscle-specific kinase) antibodies and is present in <10% of patients, more frequently in women. There are 2 presentations with MuSK antibodies, one similar to typical myasthenia gravis (around 50%) and another with severe craniobulbar weakness and atrophy that affects principally neck, shoulder and respiratory muscles. The patients with MuSK tend to have a more severe disease manifestation.
Of those patients who are seronegative for antibodies initially, around 15% will have positive antibodies when tested a year later.
Electrodiagnostic studies are performed in seronegative cases or when deemed necessary. Repetitive stimulation testing is performed at slow rates (2-5 Hz), and is positive if there is a decrease in the compound muscle action potential of >10% between the first and fourth or fifth stimulation.
Another test performed is a chest CT with contrast to detect the presence of a thymoma or thymic hyperplasia.
Treatment
The initial treatment of all patients with myasthenia gravis is with pyridostigmine, which is an acetylcholinesterase inhibitor. It produces relief of symptoms by increasing the amount of acetylcholine available in the neuromuscular junction. The dosage is titrated upwards until clinical benefit is obtained or side effects appear (abdominal cramping, diarrhea, increased salivation, increased sweating, bradycardia).
The next group of medications used for the treatment are immunosuppressants. The aim with these medications is to induce and maintain long term remission.
The first line medication are corticosteroids, usually prednisone or prednisolone. Either a relatively low dose is started with gradual increase up to clinical improvement or a high dose is started with gradual decrease after clinical improvement has been achieved. With corticosteroids, the improvement in the patient’s condition is observed relatively quickly.
Due to significant side effects from corticosteroids, a second group of medications is used with the purpose of decreasing significantly the dosage of corticosteroids.
Azathioprine is usually the first medication in this group that is used, which usually has good results and permits the gradual tapering of steroids. Patience is needed, as the effects of azathioprine will show after the slow gradual increase in dosage is completed, and it needs months.
Other steroid sparing immunosuppressive medications used are mycophenolate mophetil, methotrexate and cyclophosphamide. Rituximab, which is a chimeric monoclonal antibody that targets the B cell lymphocyte surface CD20 antigen, is also considered effective.
Exacerbations or a myasthenia gravis crisis can be treated with plasma exchange or with intravenous immunoglobulins.
In patients with refractory myasthenia gravis not responding to standard immunosupressive treatment, 2 new classes of medications are available. These are the complement inhibitors (eculizumab, ravulizumab and zilucoplan) and FcRn inhibitors (efgartigimod).
Patients who have a thymoma should have it surgically removed.
Patients less than 50 years with generalized myasthenia gravis with positive acetylcholine receptor antibodies and with non-thymoma on chest CT scan, should have a thymectomy within 4 months of the diagnosis. In patients with age 50-65 years early thymectomy is considered if early improvement in symptoms is not achieved or significant side effects from treatment are present.
Κωνσταντίνος Τάκης, MD, FAHA 