Myasthenia gravis

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. People can develop MG at any age. For unknown reasons, it is most commonly diagnosed in women younger than age 40 and men older than age 60. It is uncommon in children, but some infants born to women with MG have signs and symptoms of the condition for the first few days or weeks of life. This temporary occurrence of symptoms is called transient neonatal myasthenia gravis.

Photograph of a person showing right partial ptosis (left picture), the left lid shows compensatory pseudo lid retraction because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation): Right picture: after an edrophonium test, note the improvement in ptosis.

Cause

Researchers believe that variations in particular genes may increase the risk of myasthenia gravis, but the identity of these genes is unknown. Many factors likely contribute to the risk of developing this complex disorder.

Myasthenia gravis is an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's own tissues and organs. In myasthenia gravis, the immune system disrupts the transmission of nerve impulses to muscles by producing a protein called an antibody that attaches (binds) to proteins important for nerve signal transmission. Antibodies normally bind to specific foreign particles and germs, marking them for destruction, but the antibody in myasthenia gravis attacks a normal human protein. In most affected individuals, the antibody targets a protein called acetylcholine receptor (AChR); in others, the antibodies attack a related protein called muscle-specific kinase (MuSK). In both cases, the abnormal antibodies lead to a reduction of available AChR.

The AChR protein is critical for signaling between nerve and muscle cells, which is necessary for movement. In myasthenia gravis, because of the abnormal immune response, less AChR is present, which reduces signaling between nerve and muscle cells. These signaling abnormalities lead to decreased muscle movement and the muscle weakness characteristic of this condition. It is unclear why the immune system malfunctions in people with myasthenia gravis.

Inheritance

In most cases, myasthenia gravis is not inherited and occurs in people with no history of the disorder in their family. About 3 to 5 percent of affected individuals have other family members with myasthenia gravis or other autoimmune disorders, but the inheritance pattern is unknown.

Symptoms

Myasthenia gravis (MG) causes muscle weakness and can affect any voluntary muscle. Voluntary muscles are the muscles that we directly control to make our body do things like walk, run, write, throw, lift, smile, and chew. In MG, the most commonly affected muscles are the muscles that control eye and eyelid movement, facial expressions, and swallowing. The degree of muscle weakness varies from person to person. People with more severe disease may have many muscles affected, including the muscles that control breathing. People with mild disease may have only one muscle group involved, such as the eye muscles. In general, signs and symptoms of MG may include:

• Drooping of one or both eyelids (ptosis)
• Blurred or double vision (diplopia)
• Unstable or waddling gait (manner of walking)
• Weakness in the arms, hands, fingers, legs, and neck
• Change in facial expression
• Difficulty swallowing and shortness of breath
• Impaired speech (dysarthria)

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms Abnormality of the thymus

• Acetylcholine receptor antibody positivity
• Bulbar palsy
• Diplopia(Double vision)
• Dysarthria(Difficulty articulating speech)
• Dysphagia(Poor swallowing)
• Dyspnea(Trouble breathing)
• Muscle specific kinase antibody positivity
• Myositis(Muscle inflammation)
• Ophthalmoparesis(Weakness of muscles controlling eye movement)
• Ptosis(Drooping upper eyelid)
• Single fiber EMG abnormality

5%-29% of people have these symptoms

• Glycosuria(Glucose in urine)
• Hashimoto thyroiditis
• Hearing impairment(Deafness)
• Hyperacusis
• Hyperthyroidism(Overactive thyroid)
• Paresthesia(Pins and needles feeling)
• Primary adrenal insufficiency
• Raynaud phenomenon
• Rheumatoid arthritis
• Systemic lupus erythematosus

1%-4% of people have these symptoms

• Acrocyanosis(Persistent blue color of hands, feet, or parts of face)
• Hemolytic anemia
• Hepatitis(Liver inflammation)
• Psychosis
• Pure red cell aplasia
• Seizure

Diagnosis

Blood tests If the diagnosis is suspected, serology can be performed: One test is for antibodies against the acetylcholine receptor;the test has a reasonable sensitivity of 80–96%, but in ocular myasthenia, the sensitivity falls to 50%. A proportion of the people without antibodies against the acetylcholine receptor have antibodies against the MuSK protein. In specific situations, testing is performed for Lambert-Eaton syndrome.

Electrodiagnostics A chest CT-scan showing a thymoma (red circle)

Muscle fibers of people with MG are easily fatigued, which the repetitive nerve stimulation test can help diagnose. In single-fiber electromyography (SFEMG), which is considered to be the most sensitive (although not the most specific) test for MG, a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers. Two muscle fibers belonging to the same motor unit are identified, and the temporal variability in their firing patterns is measured. Frequency and proportion of particular abnormal action potential patterns, called "jitter" and "blocking", are diagnostic. Jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.

Ice test Applying ice for two to five minutes to the muscles reportedly has a sensitivity and specificity of 76.9% and 98.3%, respectively, for the identification of MG. Acetylcholinesterase is thought to be inhibited at the lower temperature, and this is the basis for this diagnostic test. This generally is performed on the eyelids when a ptosis is present, and is deemed positive if a ≥2 mm rise in the eyelid occurs after the ice is removed.

Edrophonium test This test requires the intravenous administration of edrophonium chloride or neostigmine, drugs that block the breakdown of acetylcholine by cholinesterase (acetylcholinesterase inhibitors). This test is no longer typically performed, as its use can lead to life-threatening bradycardia (slow heart rate) which requires immediate emergency attention.Production of edrophonium was discontinued in 2008.

Imaging A chest X-ray may identify widening of the mediastinum suggestive of thymoma, but computed tomography (CT) or magnetic resonance imaging (MRI) are more sensitive ways to identify thymomas and are generally done for this reason.MRI of the cranium and orbits may also be performed to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.

Pulmonary function test The forced vital capacity may be monitored at intervals to detect increasing muscular weakness. Acutely, negative inspiratory force may be used to determine adequacy of ventilation; it is performed on those individuals with MG.

Treatment

Treatment is by medication and/or surgery. Medication consists mainly of acetylcholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process. Thymectomy is a surgical method to treat MG. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Eculizumab (Brand name: Soliris)eculizumab (Soliris) was approved for the treatment of adult patients with generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive.

Myasthenia gravis Resources
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NIH genetic and rare disease info

• NIH info on Myasthenia gravis

Myasthenia gravis is a rare disease.