myasthenia gravis

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Myasthenia Gravis

 

Definition

Myasthenia gravis is an autoimmune disease that causes muscle weakness.

Description

Myasthenia gravis (MG) affects the neuromuscular junction, interrupting the communication between nerve and muscle, and thereby causing weakness. A person with MG may have difficulty moving their eyes, walking, speaking clearly, swallowing, and even breathing, depending on the severity and distribution of weakness. Increased weakness with exertion, and improvement with rest, is a characteristic feature of MG.
About 30,000 people in the United States are affected by MG. It can occur at any age, but is most common in women who are in their late teens and early twenties, and in men in their sixties and seventies.

Causes and symptoms

Myasthenia gravis is an autoimmune disease, meaning it is caused by the body's own immune system. In MG, the immune system attacks a receptor on the surface of muscle cells. This prevents the muscle from receiving the nerve impulses that normally make it respond. MG affects "voluntary" muscles, which are those muscles under conscious control responsible for movement. It does not affect heart muscle or the "smooth" muscle found in the digestive system and other internal organs.
A muscle is stimulated to contract when the nerve cell controlling it releases acetylcholine molecules onto its surface. The acetylcholine lands on a muscle protein called the acetylcholine receptor. This leads to rapid chemical changes in the muscle which cause it to contract. Acetylcholine is then broken down by acetylcholinesterase enzyme, to prevent further stimulation.
In MG, immune cells create antibodies against the acetylcholine receptor. Antibodies are proteins normally involved in fighting infection. When these antibodies attach to the receptor, they prevent it from receiving acetylcholine, decreasing the ability of the muscle to respond to stimulation.
Why the immune system creates these self-reactive "autoantibodies" is unknown, although there are several hypotheses:
  • During fetal development, the immune system generates many B cells that can make autoantibodies, but B cells that could harm the body's own tissues are screened out and destroyed before birth. It is possible that the stage is set for MG when some of these cells escape detection.
  • Genes controlling other parts of the immune system, called MHC genes, appear to influence how susceptible a person is to developing autoimmune disease.
  • Infection may trigger some cases of MG. When activated, the immune system may mistake portions of the acetylcholine receptor for portions of an invading virus, though no candidate virus has yet been identified conclusively.
  • About 10% of those with MG also have thymomas, or benign tumors of the thymus gland. The thymus is a principal organ of the immune system, and researchers speculate that thymic irregularities are involved in the progression of MG.
Some or all of these factors (developmental, genetic, infectious, and thymic) may interact to create the autoimmune reaction.
The earliest symptoms of MG often result from weakness of the extraocular muscles, which control eye movements. Symptoms involving the eye (ocular symptoms) include double vision (diplopia), especially when not gazing straight ahead, and difficulty raising the eyelids (ptosis). A person with ptosis may need to tilt their head back to see. Eye-related symptoms remain the only symptoms for about 15% of MG patients. Another common early symptom is difficulty chewing and swallowing, due to weakness in the bulbar muscles, which are in the mouth and throat. Choking becomes more likely, especially with food that requires extensive chewing.
Weakness usually becomes more widespread within several months of the first symptoms, reaching their maximum within a year in two-thirds of patients. Weakness may involve muscles of the arms, legs, neck, trunk, and face, and affect the ability to lift objects, walk, hold the head up, and speak.
Symptoms of MG become worse upon exertion, and better with rest. Heat, including heat from the sun, hot showers, and hot drinks, may increase weakness. Infection and stress may worsen symptoms. Symptoms may vary from day to day and month to month, with intervals of no weakness interspersed with a progressive decline in strength.
"Myasthenic crisis" may occur, in which the breathing muscles become too weak to provide adequate respiration. Symptoms include weak and shallow breathing, shortness of breath, pale or bluish skin color, and a racing heart. Myasthenic crisis is an emergency condition requiring immediate treatment. In patients treated with anticholinesterase agents, myasthenic crisis must be differentiated from cholinergic crisis related to overmedication.
Pregnancy worsens MG in about one third of women, has no effect in one third, and improves symptoms in another third. About 12% of infants born to women with MG have "neonatal myasthenia," a temporary but potentially life-threatening condition. It is caused by the transfer of maternal antibodies into the fetal circulation just before birth. Symptoms include weakness, floppiness, feeble cry, and difficulty feeding. The infant may have difficulty breathing, requiring the use of a ventilator. Neonatal myasthenia usually clears up within a month.

Diagnosis

Myasthenia gravis is often diagnosed accurately by a careful medical history and a neuromuscular exam, but several tests are used to confirm the diagnosis. Other conditions causing worsening of bulbar and skeletal muscles must be considered, including drug-induced myasthenia, thyroid disease, Lambert-Eaton myasthenic syndrome, botulism, and inherited muscular dystrophies.
MG causes characteristic changes in the electrical responses of muscles that may be observed with an electromyogram, which measures muscular response to electrical stimulation. Repetitive nerve stimulation leads to reduction in the height of the measured muscle response, reflecting the muscle's tendency to become fatigued.
Blood tests may confirm the presence of the antibody to the acetylcholine receptor, though up to a quarter of MG patients will not have detectable levels. A chest x ray or chest computed tomography scan (CT scan) may be performed to look for thymoma.

Treatment

While there is no cure for myasthenia gravis, there are a number of treatments that effectively control symptoms in most people.
Edrophonium (Tensilon) blocks the action of acetylcholinesterase, prolonging the effect of acetylcholine and increasing strength. An injection of edrophonium rapidly leads to a marked improvement in most people with MG. An alternate drug, neostigmine, may also be used.
Pyridostigmine (Mestinon) is usually the first drug tried. Like edrophonium, pyridostigmine blocks acetylcholinesterase. It is longer-acting, taken by mouth, and well-tolerated. Loss of responsiveness and disease progression combine to eventually make pyridostigmine ineffective in tolerable doses in many patients.
Thymectomy, or removal of the thymus gland, has increasingly become standard treatment for MG. Up to 85% of people with MG improve after thymectomy, with complete remission eventually seen in about 30%. The improvement may take months or even several years to fully develop. Thymectomy is not usually recommended for children with MG, since the thymus continues to play an important immune role throughout childhood.
Immune-suppressing drugs are used to treat MG if response to pyridostigmine and thymectomy are not adequate. Drugs include corticosteroids such as prednisone, and the non-steroids azathioprine (Imuran) and cyclosporine (Sandimmune).
Plasma exchange may be performed to treat myasthenic crisis or to improve very weak patients before thymectomy. In this procedure, blood plasma is removed and replaced with purified plasma free of autoantibodies. It can produce a temporary improvement in symptoms, but is too expensive for long-term treatment. Another blood treatment, intravenous immunoglobulin therapy, is also used for myasthenic crisis. In this procedure, large quantities of purified immune proteins (immunoglobulins) are injected. For unknown reasons, this leads to symptomatic improvement in up to 85% of patients. It is also too expensive for long-term treatment.
People with weakness of the bulbar muscles may need to eat softer foods that are easier to chew and swallow. In more severe cases, it may be necessary to obtain nutrition through a feeding tube placed into the stomach (gastrostomy tube).

Prognosis

Most people with MG can be treated successfully enough to prevent their condition from becoming debilitating. In some cases, however, symptoms may worsen even with vigorous treatment, leading to generalized weakness and disability. MG rarely causes early death except from myasthenic crisis.

Prevention

There is no known way to prevent myasthenia gravis. Thymectomy improves symptoms significantly in many patients, and relieves them entirely in some. Avoiding heat can help minimize symptoms.
Some drugs should be avoided by people with MG because they interfere with normal neuromuscular function.
Drugs to be avoided or used with caution include:
  • Many types of antibiotics, including erythromycin, streptomycin, and ampicillin
  • Some cardiovascular drugs, including Verapamil, betaxolol, and propranolol
  • Some drugs used in psychiatric conditions, including chlorpromazine, clozapine, and lithium.
Many other drugs may worsen symptoms as well, so patients should check with the doctor who treats their MG before taking any new drugs.
A Medic-Alert card or bracelet provides an important source of information to emergency providers about the special situation of a person with MG. They are available from health care providers.

Resources

Organizations

Muscular Dystrophy Association. 3300 East Sunrise Drive, Tucson, AZ 85718. (800) 572-1717. http://www.mdausa.org.
Myasthenia Gravis Foundation of America. 222 S. Riverside Plaza, Suite 1540, Chicago, IL 60606. (800) 541-5454. http://www.med.unc.edu.

Key terms

Antibody — An immune protein normally used by the body for combating infection and which is made by B cells.
Autoantibody — An antibody that reacts against part of the self.
Autoimmune disease — A disease caused by a reaction of the body's immune system.
Bulbar muscles — Muscles that control chewing, swallowing, and speaking.
Neuromuscular junction — The site at which nerve impulses are transmitted to muscles.
Pyridostigmine bromide (Mestinon) — An anticholinesterase drug used in treating myasthenia gravis.
Tensilon test — A test for diagnosing myasthenia gravis. Tensilon is injected into a vein and, if the person has MG, their muscle strength will improve for about five minutes.
Thymus gland — A small gland located just above the heart, involved in immune system development.

myasthenia

 [mi″as-the´ne-ah]
muscular debility or weakness. adj., adj myasthen´ic.
myasthenia gas´trica weakness and loss of tone in the muscular coats of the stomach; atony of the stomach.
myasthenia gra´vis an autoimmune disease manifested as fatigue and exhaustion of the muscles, aggravated by activity and relieved by rest; the weakness ranges from mild to life-threatening. There is no muscular atrophy or loss of sensation. It characteristically affects the ocular and other cranial muscles and tends to fluctuate in severity. The muscular weakness is believed to be caused by the presence of circulating antibodies directed against the postsynaptic acetylcholine receptors at the neuromuscular junction; it is not clear what initiates formation of the antibodies. There also is evidence of altered cellular immunity.

Symptoms of myasthenia gravis include ptosis, diplopia, and difficulty in chewing and swallowing. Weakness of the upper and lower limbs usually is first noted when the patient tries to walk upstairs, gets up from a sitting position, raises arms over the head, or lifts a heavy object. Ventilatory deficiency due to weakness of the respiratory muscles occurs in those with a severe form of the disease. About 20 per cent of all affected patients have only ocular myasthenia; the others have some form of generalized weakness. The presence of acetylcholine receptor antibodies is elevated in patients with myasthenia gravis. Diagnosis is established when there is a favorable response to cholinergic drugs, which are inhibitors of acetylcholinesterase (an enzyme that breaks down acetylcholine); their action permits acetylcholine levels to become high enough to stimulate the postsynaptic receptors.

Children born of mothers with the disease exhibit a transient weakness that is evident at birth or may appear in the first day or so, with feeding difficulties manifested by poor sucking and swallowing abilities. They rarely have bulbar involvement, and usually recover in a week or so after birth. This condition is called neonatal myasthenia, and is related to circulating antibodies acquired from the mother while the fetus was in utero. Congenital myasthenia is also present at birth, but it may not be evident until after the first year of life. The child produces antibodies against acetylcholine receptor sites and experiences symptoms similar to those presented by myasthenia gravis patients of all ages.

The patient is started on anticholinesterase drugs, such as neostigmine or pyridostigmine, as soon as the diagnosis is confirmed. The steroid prednisone and other immunosuppressive drugs provide some relief of symptoms and longer periods of remission. thymectomy is an alternative treatment for those patients whose weakness and debility do not respond adequately to cholinergic drug therapy. plasma exchange to remove the circulating autoantibodies provides some clinical improvement. High-dose intravenous immune globulin may also be used to temporarily improve immune function.

Myasthenic crisis can develop suddenly after a systemic infection, surgery, or some other stressful event. The crisis usually is transient, but during the critical phase assisted ventilation and intensive care are needed to assure survival of the patient with respiratory failure.
Schematic drawing of the normal neuromuscular junction (A) and its simplification in myasthenia gravis (B). The antibodies bind to the acetylcholine (Ach) receptor preventing binding of the neurotransmitter (Ach). From Damjanov, 2000.
neonatal myasthenia transient myasthenia gravis (lasting a week to a month) in infants born to myasthenic women.

my·as·the·ni·a gra·vis

[MIM*254200]
a disorder of neuromuscular transmission marked by fluctuating weakness and fatigue of certain voluntary muscles, including those innervated by brainstem motor nuclei; caused by a marked reduction in the number of acetylcholine receptors in the postsynaptic membrane of the neuromuscular junction, resulting from an autoimmune mechanism.
Synonym(s): Goldflam disease

myasthenia gravis

(grăv′ĭs)
n.
A disease characterized by progressive fatigue and generalized weakness of the skeletal muscles, especially those of the face, neck, arms, and legs, caused by impaired transmission of nerve impulses following an autoimmune attack on acetylcholine receptors.

myasthenia gravis

an abnormal condition characterized by chronic fatigability and muscle weakness, especially in the face and throat, as a result of a defect in the conduction of nerve impulses at the neuromuscular junction.
observations Muscular fatigability in myasthenia gravis is caused by the inability of receptors at the myoneural junction to depolarize because of a deficiency of acetylcholine; hence the diagnosis may be made by administering an anticholinesterase drug and observing improved muscle strength and stamina. The onset of symptoms is usually gradual, with ptosis of the upper eyelids, diplopia, and weakness of the facial muscles. The weakness may then extend to other muscles innervated by the cranial nerves, particularly the respiratory muscles. Muscular exertion aggravates the symptoms, which typically vary over the course of the day. The disease occurs in younger women more often than in older women and in men over 60 years of age more often than in younger men.
interventions Anticholinesterase drugs are given. The edrophonium test is used to determine the optimal maintenance dose. Neostigmine or pyridostigmine is the drug most often used.
nursing considerations Physical activity is restricted and bed rest encouraged. Anticholinesterase drugs are usually administered before meals, and the patient is monitored for toxic side effects. Myasthenic crisis may require emergency respiratory assistance. The patient's diet may have to be adjusted if the ability to chew and swallow is affected.
enlarge picture
Myasthenia gravis: typical facial expression

myasthenia gravis

An autoimmune disorder characterised by weakness and muscle fatigue.

Clinical findings
Ptosis and diplopia (ocular myasthenia), weakness, skeletal muscle fatigability; generalised in most patients, often proximal.
  
Epidemiology
5–12.5/105 (± 25,000 active cases); peak incidence: women 2nd–3rd decades, men 6–7th decades.
 
Grades
Based on severity, ranging from focal disease (grade I) to life-threatening crisis with impaired respiration (grade IV).
 
Diagnosis
Anticholinesterase (Tensilon test), repetitive nerve stimulation, assay for anti-acetylcholine receptors, single-fibre EMG.
 
Associated conditions
Thymoma, thymic hyperplasia, other autoimmune diseases (e.g., thyroiditis, Graves’ disease, rheumatoid arthritis, SLE).
 
Management
Anticholinergics (e.g., pyridostigmine), thymectomy, immunosuppressants (corticosteroids, azathioprine, cyclosporine), immunotherapy (IV immunoglobulin, plasma exchange).

myasthenia gravis

Neurology An autoimmune disease characterized by weakness and muscle fatigue Epidemiology 5-12.5/105–± 25,000 active cases, peak incidence ♀ 2nd–3rd decade, ♂ 6-7th decade Clinical Ptosis and diplopia–ocular MG, weakness, skeletal muscle fatigability, generalized in most Pts, often proximal Grades Based on severity, ranging from focal disease–grade I to life-threatening crisis with impaired respiration–grade IV Diagnosis Anticholinesterase–Tensilon test, repetitive nerve stimulation, anti-acetylcholine receptor assay, single-fiber EMG Associated conditions Thymoma, thymic hyperplasia, autoimmune diseases–eg, thyroiditis, Graves' disease, rheumatoid arthritis, SLE Treatment Anticholinergics–eg, pyridostigmine; thymectomy, immunosuppressants–corticosteroids, azathioprine, cyclosporine, immunotherapy–IV immunoglobulin, plasma exchange

my·as·the·ni·a gra·vis

(mīas-thēnē-ă grāvis)
Disorder of neuromuscular transmission, marked by fluctuating weakness, especially of the oculofacial muscles and the proximal limb muscles; the weakness characteristically increases with activity; due to an immunologic disorder.
Synonym(s): Goldflam disease.

myasthenia gravis

An autoimmune disease caused by an abnormal antibody that affects the sites (myoneural junctions) at which motor nerves stimulate muscles to contract by releasing the NEUROTRANSMITTER acetylcholine. The effect is a rapidly worsening weakness of muscles with use. There is drooping of the eyelids, double vision, difficulty in swallowing, coughing and speaking and general weakness of the limbs. Treatment is by the use of drugs that antagonize the enzyme (acetylcholinesterase) that breaks down acetylcholine. These include NEOSTIGMINE and PYRIDOSTIGMINE. Removal of the thymus gland can be helpful as can removal of the antibodies from the blood (PLASMAPHERESIS).

Goldflam,

Samuel V., Polish neurologist, 1852-1932.
Erb-Goldflam disease - Synonym(s): Goldflam disease
Goldflam disease - disorder of neuromuscular transmission, marked by fluctuating weakness, of oculofacial and proximal limb muscles. Synonym(s): Erb-Goldflam disease; Goldflam symptom complex; Hoppe-Goldflam disease; myasthenia gravis
Goldflam symptom complex - Synonym(s): Goldflam disease
Hoppe-Goldflam disease - Synonym(s): Goldflam disease

Wilks,

Sir Samuel, English physician, 1824-1911.
Wilks syndrome - Synonym(s): myasthenia gravis

disease

pathogenic entity characterized by an identifiable aetiological agent, group of signs and symptoms and/or consistent anatomical alterations; see syndrome
Goldflam's disease; myasthenia gravis autoimmune disease caused by synaptic enzyme deficiency; characterized by chronic, progressive, muscular weakness (without atrophy), especially of upper limbs, and inability to sustain muscular actions, e.g. smiling, maintain eyelids open; patients with myasthenia gravis may be treated with steroids and anticholinesterases (and thus show drug-induced hyperhidrosis)

myasthenia gravis

An autoimmune disease affecting neuromuscular junctions characterized by muscle weakness and fatigability. It is due to a destruction of acetylcholine receptors in the postsynaptic membrane of the neuromuscular junction. In the eye it may result in ptosis, diplopia, keratoconjunctivitis sicca due to improper blinking and consequent dryness of the cornea, and eyelid twitch due to a paresis of the extraocular muscles. Drugs that inhibit acetylcholinesterase (e.g. neostigmine) and prolong the excitatory action of acetylcholine are used in the treatment of this disease. See ocular dysmetria; chronic progressive external ophthalmoplegia; Cogan's lid twitch sign.

my·as·the·ni·a gra·vis

(mīas-thēnē-ă grāvis) [MIM*254200]
Disorder of neuromuscular transmission marked by fluctuating weakness and fatigue of some voluntary muscles.

myasthenia gravis (mī´asthē´nēə grā´vis),

n an autoimmune disease resulting in incomplete communication between the nerves, thereby causing fatigue and weakness of the muscles, with the facial muscles usually among the first affected.

myasthenia

primary skeletal muscle weakness in the absence of nervous system lesions or myositis or myodystrophy. For the most part the weakness is reversible or temporary. Examples amongst animal diseases are myasthenia gravis, hypocalcemia, hypopotassemia, hypoglycemia, and many plant toxins that cause the so-called staggers syndromes in food animals.

angiosclerotic myasthenia
excessive muscular fatigue due to vascular changes; intermittent claudication.
myasthenia gastrica
weakness and loss of tone in the muscular coats of the stomach; atony of the stomach.
myasthenia gravis
a syndrome of muscular weakness that is aggravated by activity and relieved by rest. There is no muscular atrophy or loss of sensation. Affected dogs and cats show predominantly episodic weakness, but various other manifestations, such as laryngeal paralysis, dysphagia and megaesophagus, may also be seen. Clinical signs are rapidly reversed by anticholinesterase drugs and this is used as a diagnostic test for the disease. It may be congenital or acquired as an autoimmune disease, inherited in some breeds.
paraneoplastic myasthenia gravis
seen in association with neoplasms and other lesions of the thymus.