Myasthenia gravis

Myasthenia gravis (sometimes abbreviated MG; from the Greek myastheneia, lit. 'muscle weakness', and Latin gravis, lit. 'serious') is a neuromuscular disease leading to fluctuating weakness and fatiguability. At about 14 cases per 100,000 (in the U.S.), it is one of the best known autoimmune disorders. The antigens and basic disease mechanisms are known. Weakness is caused by circulating antibodies that block acetylcholine receptors or the MuSK protein at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated with immunosuppression and cholinesterase inhibitors.

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 can 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 (Bedlack & Sanders 2000).

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 or MuSK protein. 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 syndrome, in which other antibodies (against a voltage-gated calcium channel) are frequently found.

Single-fiber electromyography and repetitive nerve stimulation

Muscle fibers of patients with myasthenia gravis are easily fatigued, and thus do not respond as well as muscles in healthy individuals to repeated stimulation. By repeatedly stimulating a muscle with electrical impulses, the fatiguability of the muscle can be measured. This is called the repetitive nerve stimulation test. In single fiber electromyography, which is considered to be the most sensitive(although not the most specific) test for myasthenia gravis, a thin needle electrode is inserted into a muscle to record the electric potentials of individual muscle fibers. By finding two muscle fibers belonging to the same motor unit and measuring the temporal variability in their firing patterns(ie their 'jitter'), the diagnosis can be made.

Edrophonium test

The "edrophonium test" is infrequently performed to identify MG; its application is limited to the situation when other investigations do not yield a conclusive diagnosis. 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.

Imaging

A chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton due to a lung tumor) and comorbidity. It may also identify widening of the mediastinum suggestive of thymoma, but computed tomography (CT) or magnetic resonance imaging (MRI) are more senstive ways to identify thymomas, and these are generally done for this reason.

Pulmonary function test

Spirometry (lung function testing) may be performed to assess respiratory function if there are concerns about a patient's ability to breathe adequately. 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, and other abnormalities are frequently found. There are various theories that explain why thymoma may predispose to MG. The disease process generally remains stationary after thymectomy (removal of the thymus) for tumor.

In MG, the autoantibodies are directed most commonly 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.

It has recently been realized that a second category of gravis is due to auto-antibodies against MuSK (Muscle Specific Kinase), a receptor which is required for the formation of the neuromuscular junction (NMJ). Antibodies against MuSK inhibit the signaling of MuSK normally induced by its nerve-derived ligand, agrin. The result is a decrease in patency of the NMJ, and the consequent symptoms of myastenia gravis.

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. The prevalence in the United States is estimated at 14 cases per 100,000, or roughly 36,000 cases in the USA. ^*

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

Scherer K, Bedlack RS, Simel DL. Does this patient have myasthenia gravis? JAMA 2005;293:1906-14. PMID 15840866.
Bedlack RS, Sanders DB. How to handle myasthenic crisis. Essential steps in patient care. Postgrad Med 2000;107:211-4, 220-2. Fulltext. PMID 10778421.

External links

Original version based on a US government factsheet
The Myasthenia Gravis Foundation of America
The Myasthenia Gravis Association (MGA) in the United Kingdom & the Republic of Ireland

Autoimmune diseases | Neurology

Gourt Home::Gourt :: Myasthenia gravis