Myasthenia gravis
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Myasthenia gravis (MG, Latin: "grave muscle weakness") is a neuromuscular disease leading to fluctuating weakness and fatiguability. It is one of the best known autoimmune disorders and the antigens and disease mechanisms have well been identified. Weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated with immunosuppression and cholinesterase inhibitors.
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Signs and symptoms
The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often, but not always, involved in the disorder. The muscles that control breathing and neck and limb movements may also be affected.
Although myasthenia gravis may affect any voluntary muscle, muscles that control eye and eyelid movement, facial expression, and swallowing are most frequently affected. The onset of the disorder may be sudden or rapid. Symptoms often are not immediately recognized as myasthenia gravis; a proportion only receives a diagnosis after more than a year.
In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in myasthenia gravis varies greatly among patients, ranging from a localized form, limited to eye muscles (ocular myasthenia), to a severe or generalized form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in type and severity, may include asymmetrical ptosis (a drooping of one or both eyelids), diplopia (blurred or double vision) due to weakness of the muscles that control eye movements, unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, dysphagia (difficulty in swallowing) and shortness of breath, and dysarthria (impaired speech, often nasal due to weakness of the pharyngeal muscles).
A myasthenic crisis may give rise to a generalized paralysis, including those of the respiratory muscles, and assisted ventilation may be required to sustain life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress.
Diagnosis
Myasthenia can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders (Scherer et al 2005).
A thorough physical examination can reveal easy fatiguability, with the weakness improving after rest and worsening again on repeat of the exertion testing. Applying ice to the weak muscle groups may characteristically improve the weakness.
Blood tests
If the diagnosis is suspected, serology can be performed in a blood test to identify antibodies against the acetylcholine receptor. The test has a reasonable sensitivity of 80-96%, but in MG limited to the eye muscles (ocular myasthenia) the test may be negative in up to 50% of the cases. Often, parallel testing is performed for Lambert-Eaton myasthenic syndrome, in which other antibodies (against a voltage-gated calcium channel) are frequently found.
Edrophonium test
The "edrophonium test" is frequently performed to identify MG. This test requires the intravenous administration of edrophonium chloride (Tensilon®), a drug that blocks the breakdown of acetylcholine by cholinesterase and temporarily increases the levels of acetylcholine at the neuromuscular junction. In people with myasthenia gravis involving the eye muscles, edrophonium chloride will briefly relieve weakness. Other methods to confirm the diagnosis include a version of nerve conduction study which tests for specific muscle fatigue by repetitive nerve stimulation. This test records weakening muscle responses when the nerves are repetitively stimulated, and helps to differentiate nerve disorders from muscle disorders. Repetitive stimulation of a nerve during a nerve conduction study may demonstrate decrements of the muscle action potential due to impaired nerve-to-muscle transmission.
Single-fiber electromyography
A different test called single fiber electromyography (EMG), in which single muscle fibers are stimulated by electrical impulses, can also detect impaired nerve-to-muscle transmission. EMG measures the electrical potential of muscle cells. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated electrical stimulation compared to muscles from normal individuals.
Imaging
A chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton due to a lung tumor) and may also identify widening of the mediastinum suggestive of thymoma. Performing computed tomography (CT) or magnetic resonance imaging (MRI) is a more senstive way to identify thymomas.
Pulmonary function test
Spirometry (lung function testing) is performed to assess respiratory function. Severe myasthenia (myasthenic crisis) may cause respiratory failure due to exhaustion of the respiratory muscles.
Pathophysiology
Myasthenia gravis is an autoimmune disease: it features antibodies directed against the body's own proteins. While in various similar diseases the disease has been linked to a cross-reaction with an infective agent, there is no known causative pathogen that could account for myasthenia. There is a slight genetic predisposition: particular HLA types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to 25% have a concurrent thymoma, a tumor (either benign or malignant) of the thymus. There are various theories that explain why thymoma may predispose to MG; the disease process often improves after resection of the tumor.
In MG, the autoantibodies are directed against the acetylcholine receptor (nicotinic type), the receptor in the motor end plate for the neurotransmitter acetylcholine that stimulates muscular contraction. Some forms of the antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors, either by complement fixation or by inducing the muscle cell to eliminate the receptors through endocytosis.
In normal muscle contraction, cumulative activation of the ACh receptor leads to influx of sodium and calcium. Only when the levels of these electrolytes inside the muscle cell is high enough will it contract. Decreased numbers of functioning receptors therefore impairs muscular contraction.
Epidemiology
Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects young adult women (under 40) and older people of both sexes (over 60), but it can occur at any age.
In neonatal myasthenia, the fetus may acquire immune proteins (antibodies) from a mother affected with myasthenia gravis. Generally, cases of neonatal myasthenia gravis are transient (temporary) and the child's symptoms usually disappear within few weeks after birth. Other children develop myasthenia gravis indistinguishable from adults.
Myasthenia gravis is not directly inherited nor is it contagious. Occasionally, the disease may occur in more than one member of the same family. Rarely, children may show signs of congenital myasthenia or congenital myasthenic syndrome. These are not autoimmune disorders, but are caused by defective genes that control proteins in the acetylcholine receptor or in acetylcholinesterase.
Treatment
Myasthenia gravis can usually be controlled with medication. Medication is used for two different endpoints:
- Direct improvement of the weakness
- Reduction of the autoimmune process
Muscle function is improved by cholinesterase inhibitors, such as neostigmine and pyridostigmine. These slow the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor.
Immunosuppressive drugs such as prednisone, ciclosporin and azathioprine may be used. If the myasthenia is serious (myasthenic crisis), plasmapheresis is used to remove the putative antibody from the circulation. Similarly, intravenous immunoglobulins (IVIg) is used to bind the circulating antibodies.
Thymectomy, the surgical removal of the thymus gland (which is abnormal in myasthenia gravis patients), improves symptoms in more than 50 percent of patients, even in those without thymoma. Some patients are cured by thymectomy, suggesting that the thymus plays a significant role in the pathogenesis of myasthenia.
Prognosis
With treatment, most patients have a near-normal quality of life and no significant problems. Some cases of myasthenia gravis may go into remission temporarily and muscle weakness may disappear completely so that medication can be discontinued. Stable, long-lasting complete remissions are the goal of thymectomy.
References
- Original version based on a US government factsheet (http://www.ninds.nih.gov/health_and_medical/pubs/myasthenia_gravis.htm)
- Template:OMIM
- Scherer K, Bedlack RS, Simel DL. Does this patient have myasthenia gravis? JAMA 2005;293:1906-14. PMID 15840866.de:Myasthenia gravis