myasthenia gravis

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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.

— Richard Robinson

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.

[New Latin : MYASTHENIA + Latin gravis, heavy, severe.]

Definition

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by fatigue and muscular weakness, especially in the face and neck, that results from a breakdown in the normal communication between nerves and muscles caused by the deficiency of acetylcholine at the neuromuscular (nerve-muscle) junctions. MG is the most common primary disorder of neuromuscular transmission.

Description

MG is a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. The hallmark of this disease is muscle weakness that increases during periods of activity and improves after periods of rest. Muscles that control eye and eyelid movements, facial expression, chewing, talking, and swallowing are often, but not always, involved. The muscles that control breathing and neck and limb movements may also be affected.

Myasthenia gravis can be classified according to which skeletal muscles are affected. Within a year of onset, approximately 85–90% of affected persons develop generalized MG, which is characterized by weakness in the trunk, arms, and legs. About 10–15% of patients have weakness only in muscles that control eye movement. This type is called ocular myasthenia gravis.

Other types of MG include congenital MG, an inherited condition caused by a genetic defect, and transient neonatal, which occurs in infants born from mothers who have MG. Congenital MG develops at or shortly after birth and causes generalized symptoms.

Demographics

Myasthenia gravis occurs in all ethnic groups and both genders. The prevalence of MG in the United States is estimated to be 14 per 100,000 population, which equals approximately 36,000 cases in the United States. However, this disease is probably under diagnosed and the prevalence may be higher. Previous studies showed that women are more often affected than men. The most common age at onset is the second and third decades in women and the seventh and eighth decades in men. As the population ages, the average age of onset has increased correspondingly, and now males are considered to be more often affected than females, and the onset of symptoms is usually after age 50.

Causes and symptoms

Myasthenia gravis is an autoimmune disease caused by abnormal antibodies carried in the blood stream. Nerves release a chemical called acetylcholine (ACh) that activates receptors on muscles to trigger contraction. The normal neuromuscular junction releases ACh from the motor nerve terminal in discrete packages (quanta). The ACh quanta diffuse across the synaptic cleft and bind to receptors on the folded muscle end-plate membrane. Stimulation of the motor nerve releases many ACh quanta that depolarize the muscle end-plate region and then the muscle membrane, causing muscle contraction.

The myasthenia antibodies interfere with this process by binding to specific sites on the surface of the muscles, the post-synaptic muscle membrane is distorted and simplified, having lost its normal folded shape. The most common antibodies are directed against the muscle acetylcholine receptor (AChR). ACh is released normally, but its effect on the post-synaptic membrane is reduced. The post-junctional membrane is less sensitive to applied ACh, and the probability that any nerve impulse will cause a muscle action potential is reduced.

Ten percent of patients with MG have a tumor in the thymus, (a thymoma) that is usually benign, and 70% have changes (germinal centers) that indicate an active immune response. These are areas within lymphoid tissue where B-cells interact with helper T-cells to produce antibodies. Because the thymus is the central organ for immunological self-tolerance, it is reasonable to suspect that thymic abnormalities cause the breakdown in tolerance that leads to an immune-mediated attack on AChR in this disease. The thymus contains all the necessary elements for the beginnings of MG: myoid cells that express the AChR antigen, antigen presenting cells, and immunocompetent T-cells. However, it is still uncertain whether the role of the thymus in the pathogenesis of disease is primary or secondary.

There are very rare genetic abnormalities that cause problems similar to myasthenia gravis. These diseases are called congenital or inherited myasthenias and usually are present in infants. MG 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 (present at birth) 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 acetyl-cholinesterase. In neonatal myasthenia that develops in 10–20% of infants born to mothers who have MG, the fetus may acquire immune proteins (antibodies) from a mother affected with MG. Generally, cases of neonatal myasthenia are transient and the child's symptoms usually disappear within few weeks after birth.

Although MG 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. Symptoms often are not immediately recognized as myasthenia gravis. 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 this disease 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 a drooping of one or both eyelids (ptosis), blurred or double vision (diplopia) 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, difficulty in swallowing and shortness of breath, and impaired speech (dysarthria).

Diagnosis

A delay in diagnosis of one or two years is not unusual in cases of MG. Because weakness is a common symptom of many other disorders, the diagnosis is often missed in people who experience mild weakness or in those individuals whose weakness is restricted to only a few muscles. The first steps of diagnosing MG include a review of the individual's medical history, and physical and neurological examinations. The signs a physician must look for are impairment of eye movements or muscle weakness without any changes in the individual's ability to feel things. If the physician suspects MG, several tests are available to confirm the diagnosis.

The Edrophonium Chloride (Tensilon) Test

This approach requires the intravenous administration of edrophonium chloride or Tensilon(r), a drug that temporarily increases the levels of acetylcholine at the neuromuscular junction. In people with myasthenia gravis involving the eye muscles, the drug will chloride will briefly relieve weakness.

Antibodies Against Acetylcholine Receptor (AChR)

In general, an elevated concentration of AChR binding antibodies in a patient with compatible clinical features confirms the diagnosis of MG, but normal antibody concentrations do not exclude the diagnosis.

Repetitive Nerve Stimulation (RNS)

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 faults of the muscle action potential (CMAP) due to impaired nerve-to-muscle transmission. A significant decrement to RNS in either a hand or shoulder muscle is found in about 60% of patients with MG.

Single fiber electromyogram (SFEMG)

SFEMG is the most sensitive clinical test of neuromuscular transmission and shows increased jitter in some muscles in almost all patients with myasthenia gravis. Jitter is greatest in weak muscles, but may be abnormal even in muscles with normal strength. Patients with mild or purely ocular (eye) muscle weakness may have increased jitter only in facial muscles. Increased jitter is a nonspecific sign of abnormal neuromuscular transmission and can also be seen in other motor diseases.

Computed tomography (CT) or magnetic resonance imaging (MRI)

Computed tomography (CT) or magnetic resonance imaging (MRI) may be used to identify an abnormal thymus gland or the presence of a thymoma. Pulmonary function testing, which measures breathing strength, helps to predict whether respiration may fail and lead to a myasthenic crisis.

Treatment team

The treatment team is normally composed of a neurologist, a nutritionist (dietary advice), a speech pathologist, a pulmonologist, a geneticist, a neurologist, a dentist, a otolaryngologist, a physical therapist, and nurses.

Treatment

Treatment regimens for myasthenia gravis are practical rather than curative. Treatment decisions are based on knowledge of the natural history of disease in each patient and the predicted response to a specific form of therapy. Treatment goals must be individualized according to the severity of disease, the patient's age and sex, and the degree of functional impairment. The response to any form of treatment is difficult to assess because the severity of symptoms fluctuates. Spontaneous improvement, even remissions, occur without specific therapy, especially during the early stages of the disease.

Cholinesterase inhibitors

Cholinesterase inhibitors result in increased ACh accumulation at the neuromuscular junction and prolongs its effect. These drugs cause considerable improvement in some patients and little to none in others. Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin) are the most commonly prescribed cholinesterase inhibitors. No fixed dosage schedule suits all patients. The need for cholinesterase inhibitors varies from day to day and during the same day in response to infection, menstruation, emotional stress, and hot weather. Different muscles respond differently; with any dose, certain muscles become stronger, others do not change, and still others become weaker. Adverse effects of cholinesterase inhibitors include gastrointestinal complaints: queasiness, loose stools, nausea, vomiting, abdominal cramps, and diarrhea.

Thymectomy

Thymectomy (removal of the thymus) is recommended for most people with myasthenia gravis. The greatest benefit from the surgery generally occurs two to five years afterwards. However, the response is relatively unpredictable and significant impairment may continue for months or years after surgery. The best responses to thymectomy are in young people early in the course of the disease, but improvement can occur even after 30 years of symptoms. Persons with disease onset after the age of 60 rarely show substantial improvement from thymectomy. Patients with thymomas (tumor on the thymus) do not respond as well to thymectomy as do patients without them.

Corticosteroids

Marked improvement or complete relief of symptoms occurs in more than 75% of people treated with prednisone, and some improvement occurs in most of the rest. Much of the improvement occurs in the first six to eight weeks of therapy, but strength may increase to total remission in the months that follow. The best responses occur in patients with recent onset of symptoms, but patients with chronic disease may also respond. The severity of disease does not predict the ultimate improvement. Patients with thymoma have an excellent response to prednisone before or after removal of the tumor. About one-third of patients become weaker temporarily after starting prednisone, usually within the first seven to ten days, but this temporary weakness lasts for only a few days. The major disadvantages of chronic corticosteroid therapy are the side effects, such as weight gain and fluid retention.

Immunosuppressant drugs

Azathioprine reverses symptoms in most patients with myasthenia gravis, but the benefits are delayed by four to eight months. Once improvement begins, it is maintained for as long as the drug is given. Symptoms recur two to three months after the drug is discontinued or the dose is reduced below therapeutic levels. Patients who experience no improvement on corticosteroids may respond to azathioprine, and the reverse is also true. Sometimes, people with MG respond better to treatment with both drugs than to either one alone. Because the response to azathioprine is delayed, both drugs may be started simultaneously with the intent of rapidly tapering prednisone when azathioprine becomes effective. Approximately one-third of patients have mild dose-dependent side effects that may require dose reductions, but do not require stopping treatment.

Cyclosporine is sometimes beneficial in treating MG. Most patients with myasthenia gravis improve within two months after starting cyclosporine and improvement is maintained as long as therapeutic doses are given. Maximum improvement is achieved six months or longer after starting treatment. After achieving the maximal response, the dose is gradually reduced to the minimum that maintains improvement. Toxicity to the kidneys and hypertension are important adverse reactions of cyclosporine. Many drugs interfere with cyclosporine metabolism and should be avoided or used with caution.

Cyclophosphamide is also given intravenously and orally for the treatment of myasthenia gravis. More than half of patients receiving cyclophosphamide experience a dramatic improvement in their symptoms after one year; however, side effects are common. Life-threatening infections are an important risk for all persons taking immunosuppressant drugs.

Plasma exchange

Plasma exchange is used as a short-term intervention for patients with sudden worsening of myasthenic symptoms, to rapidly improve strength before surgery, and as a chronic intermittent treatment for patients who are refractory to all other treatments. The need for plasma exchange and its frequency of use is determined by the clinical response in the individual patient. Almost all patients with acquired MG improve temporarily following plasma exchange. Maximum improvement may be reached as early as after the first exchange or as late as the fourteenth. Improvement lasts for weeks or months and then the effect is lost unless the exchange is followed by thymectomy or immunosuppressive therapy. Most patients who respond to the first plasma exchange will respond again to subsequent courses. Repeated exchanges do not have a cumulative benefit.

Intravenous immune globulin (IVIG)

Immune globulin given intravenously results in improvement in more than half of MG patients, usually beginning within one week of therapy and lasting for several weeks or months.

Recovery and rehabilitation

Physical and occupational therapists provide strategies to help people with myasthenia gravis maintain daily activities during almost all phases of the disease. As the progression of symptoms occurs over months or years, these strategies adapt to the changing needs of the person with myasthenia gravis. For example, wheelchairs, specialized eating utensils, and positioning aids might be required during the progressive phase. When improvement is made, shower stools, rolling carts for carrying shopping items, and exercises to promote maintenance of posture can all help avoid fatigue. While the symptoms of the disease may go into remission, recovery is not said to be complete, as symptoms may recur. The longer the person remains in remission; however, the greater is the chance that the disease will not recur

Clinical trials

As of February 2004, there were two open clinical trials for MG, both sponsored by the Rush University Medical Center in Chicago, Illinois:

• Study of CellCept in the Treatment of MG: This is a multicenter, placebo-controlled study testing CellCept and prednisone as the initial form of immunotherapy in the treatment of MG. The purpose of the study is to determine if the combination of these two medications provides better control of MG symptoms compared with prednisone alone.
• Study of Etanercept Among Individuals With MG: The purpose of the study is to determine if Etanercept improves muscle strength in patients with MG.

Up-to-date information on clinical trials can be found at the United States government website for clinical trials located at .

Prognosis

Symptoms of myasthenia gravis usually progress to maximum severity within three years. After that time, persons with MG normally stabilize or improve. With treatment, the outlook for most patients with MG is bright: they will have significant improvement of their muscle weakness and they can expect to lead normal or nearly normal lives.

Many people's MG symptoms may go into remission temporarily and muscle weakness may disappear completely, so that medications can be discontinued. Stable, long-lasting complete remissions are the goal of thymus removal (thymectomy). In a few cases, the severe weakness of MG may cause a crisis (respiratory failure), which requires immediate emergency medical care. Advances in medical care have reduced the mortality rate from respiratory failure in myasthenia gravis patients to approximately three percent. Patients over the age of 40, those with a short history of severe disease, and those with thymoma tend to have less significant improvement.

Special concerns

Myasthenia gravis cannot be prevented, but avoiding the following triggers may help patients prevent exacerbations (worsening of symptoms):

• emotional stress
• exposure to extreme temperatures
• fever
• illness (e.g., respiratory infection, pneumonia, tooth abscess)
• low levels of potassium in the blood (hypokalemia; caused by diuretics, frequent vomiting)
• some medications, such as muscle relaxants, anticonvulsants, and certain antibiotics

Resources

BOOKS

Henderson, Ronald E. Attacking Myasthenia Gravis. Seattle: Court Street Press, 2002.

Icon Health Publications. The Official Patient's Sourcebook on Myasthenia Gravis: A Revised and Updated Directory for the Internet Age. San Diego: Icon Grp. Int., 2002.

OTHER

National Institute of Neurological Disorders and Stroke. "Myasthenia Gravis Fact Sheet." http://www.ninds.nih.gov/health_and_medical/pubs/myasthenia_gravis.htm (February 11, 2004).

ORGANIZATIONS

Myasthenia Gravis Foundation of America, Inc. 5841 Cedar Lake Road Suite 204, Minneapolis, MN 55416. (952) 545-9438 or (800) 541-5454; Fax: (952) 646-2028. myastheniagravis@msn.com. http://www.myasthenia.org.

Beatriz Alves Vianna

Iuri Drumond Louro

Key Terms: Antibody, Atropine, Autoantibody, Autoimmune disease, Bulbar muscles, Immunoglobulin, Malignant thymoma, Neuromuscular junction, Pyridostigmine bromide, Tensilon test, Thymectomy.

Description

Myasthenia gravis (MG) is an autoimmune disease that causes muscle weakness. It affects the neuromuscular junction, interrupting the communication between nerve and muscle, and thereby causing weakness. People 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.

MG has been associated with malignant thymoma, a disease in which cancer cells are found in the tissues of the thymus.

Causes

Myasthenia gravis is an autoimmune disease, meaning that 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 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. A definite relationship exists between MG and thymoma: of patients with MG, 15% also have thymoma, and of patients with thymoma, 50% have MG.

Treatment

While there is no cure for myasthenia gravis, there are a number of treatments that effectively control symptoms in most people. Even though no rigorously tested treatment trials have been reported and no clear consensus exists on treatment strategies, MG is one of the most treatable immune disorders. Several factors require consideration before initiating treatment, such as the severity, distribution, and rapidity of the MG progression.

Edrophonium (Tensilon) is a drug used to block 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 a standard form of 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 patient response to pyridostigmine and thymectomy is not adequate. These drugs include corticosteroids such as prednisone, and the non-steroids azathioprine (Imuran) and cyclosporine (Sandimmune).

Plasma exchange may also be performed to treat the condition or to strengthen 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. 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. There are indications that IVIg is an effective immunoglobulin for some categories of MG patients.

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).

Alternative and Complementary Therapies

No alternative therapies have been shown to be effective for the treatment of MG. Reports claiming that herbal remedies or alternative treatments alleviate or cure MG have not been corroborated by properly controlled clinical trials, which are required to evaluate the benefit of such treatments.

Among complementary MG therapies, prescription of low dose atropine can help relieve the cramping and diarrhea often caused by the drug Mestinon. Propantheline bromide (ProBanthine) is a drug similar to atropine, and it may also be prescribed to treat gastrointestinal discomfort. Caution must be taken not to take too much atropine because it cancels the beneficial effects of the anticholinesterase drugs. Ephedrine is sometimes also used with anticholinesterase therapy to strengthen the muscle tissue of MG patients.

Resources

Periodicals

Bedlack, R. S., and D. B. Sanders. "How to handle myasthenic crisis. Essential steps in patient care." Postgraduate Medicine 107 (April 2000): 211–214.

Carrieri, P. B., E. Marano, A. Perretti, and G. Caruso. "The thymus and myasthenia gravis: immunological and neurophysiological aspects." Annals of Medicine 31, Supplement 2 (October 1999): 52–56

Davitt, B. V., G. A. Fenton, and O. A. Cruz. "Childhood myasthenia." Journal of Ophthalmic and Nursing Technology 19 (March-April 2000): 74–81

—Richard Robinson; Monique Laberge, Ph.D.

A disease resulting from an abnormality in neuromuscular transmission, characterized by a fluctuating degree of muscle weakness. The weakness is usually aggravated by activity, and there is partial or complete restoration of strength after a period of rest or the administration of anticholinesterase medications.

It has been shown that the basic defect in myasthenia gravis is a reduction in the number of acetylcholine receptor sites in the postsynaptic membrane of the neuromuscular junction. It has also been shown that many myasthenic patients have immunoglobulins in the serum that partially block acetylcholine receptors. See also Autoimmunity; Immunoglobulin.

Abnormalities have been demonstrated in the thymus gland and skeletal muscle in myasthenia gravis. There is an increased incidence of thymoma in myasthenia gravis, and in those without a thymoma, hyperplasia of the germinal centers is a common finding in the thymus gland.

Although the disease affects young women more commonly, usually in the third decade, it can occur in either sex at any age. In the majority of persons, weakness affects muscles of head, neck, and limbs (generalized myasthenia), but in some the weakness is restricted to the muscles of the eyes (ocular myasthenia), in which case the disease is usually benign.

The standard treatment for myasthenia gravis has been the use of longer-acting anticholinesterase agents; thymectomy and immunosuppressive drugs are reserved for those patients with generalized myasthenia that does not respond sufficiently to these agents.

An autoimmune disease resulting in incomplete communication between the nerves, thereby causing fatigue and weakness of the muscles. This is especially important for dental personnel, as the facial muscles are usually among the first affected.

For more information on myasthenia gravis, visit Britannica.com.

Myasthenia gravis
Classification and external resources
Detailed view of a neuromuscular junction: 1. Presynaptic terminal 2. Sarcolemma 3. Synaptic vesicle 4. Nicotinic acetylcholine receptor 5. Mitochondrion
ICD-10	G70.0
ICD-9	358.0
OMIM	254200
DiseasesDB	8460
MedlinePlus	000712
eMedicine	neuro/232  emerg/325 (emergency), med/3260 (pregnancy), oph/263 (eye)
MeSH	D009157

Myasthenia gravis (literally "serious muscle-weakness"; from Greek μύς "muscle", ἀσθένεια "weakness", and Latin gravis "serious"; abbreviated MG) is a neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction,^[1] inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy. At 200–400 cases per million it is one of the less common autoimmune disorders.^[1]

Contents 1 Classification 2 Signs and symptoms 3 Pathophysiology 4 Diagnosis 4.1 Physical examination 4.2 Blood tests 4.3 Neurophysiology 4.4 Edrophonium test 4.5 Imaging 4.6 Pulmonary function test 4.7 Pathological findings 5 Associations 6 In pregnancy 7 Treatment 7.1 Medication 7.2 Plasmapheresis and IVIG 7.3 Surgery 8 Prognosis 9 Epidemiology & MG in children 10 Notable people 11 References 12 External links

Classification

The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America Clinical Classification:^[2]

• Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
• Class II: Eye muscle weakness of any severity, mild weakness of other muscles
  • Class IIa: Predominantly limb or axial muscles
  • Class IIb: Predominantly bulbar and/or respiratory muscles
• Class III: Eye muscle weakness of any severity Moderate weakness of other muscles
  • Class IIIa: Predominantly limb or axial muscles
  • Class IIIb: Predominantly bulbar and/or respiratory muscles
• Class IV: Eye muscle weakness of any severity, severe weakness of other muscles
  • Class IVa: Predominantly limb or axial muscles
  • Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation)
• Class V: Intubation needed to maintain airway

Signs and symptoms

Ptosis of the left eye.

The hallmark of myasthenia gravis is fatiguability. Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Often the physical examination is within normal limits.^[3]

The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable.

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 MG 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 (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), shortness of breath and dysarthria (impaired speech, often nasal due to weakness of the velar muscles).

In myasthenic crisis a paralysis of the respiratory muscles occurs, necessitating assisted ventilation 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.^[4] Since the heart muscle is stimulated differently, it is never affected by MG.

Pathophysiology

A juvenile thymus. It shrinks with age.

Myasthenia gravis is an autoimmune channelopathy: 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 75% of patients have an abnormality of the thymus; 25% have a thymoma, a tumor (either benign or malignant) of the thymus, and other abnormalities are frequently found. The disease process generally remains stationary after thymectomy (removal of the thymus).

The acetylcholine receptor.

In MG, the autoantibodies are directed most commonly against the nicotinic acetylcholine receptor (nAChR)^[5] , 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.

The antibodies are produced by plasma cells, derived from B cells. B-cells convert into plasma cells by T-helper cell stimulation. In order to carry out this activation T-helpers must first be activated themselves, which is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment (epitope) resting within the major histocompatibility complex of an antigen presenting cells. Since the thymus plays an important role in the development of T-cells and the selection of the TCR myasthenia gravis is closely associated with thymoma. The exact mechanisms are however not convincingly clarified although resection of the thymus (thymectomy) in MG patients without a thymus neoplasm often have positive results.

In normal muscle contraction, cumulative activation of the nAChR leads to influx of sodium ions which in turn causes depolarization of muscle cell and subsequent opening of voltage gated sodium channels. This ion influx then travels down the cell membrane via T-tubules and, via calcium channel complexes leads to the release of calcium from the sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are high enough will it contract. Decreased numbers of functioning nAChRs therefore impairs muscular contraction by limiting depolarization. In fact, MG causes the motor neuron action potential to muscular twitch ratio to vary from the non-pathological one to one ratio.

It has recently been realized that a second category of gravis is due to auto-antibodies against the MuSK protein (muscle specific kinase), a tyrosine kinase receptor which is required for the formation of the neuromuscular junction. 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 neuromuscular junction, and the consequent symptoms of MG.

People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of MG, but both the symptoms and the titer disappear when drug administration is discontinued.

MG is more common in families with other autoimmune diseases. A familial predisposition is found in 5% of the cases. This is associated with certain genetic variations such as an increased frequency of HLA-B8 and DR3. People with MG suffer from co-existing autoimmune diseases at a higher frequency than members of the general population. Of particular mention is co-existing thyroid disease where episodes of hypothyroidism may precipitate a severe exacerbation.

The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research in which might eventually lead to new treatment options.^[6]

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.^[3] 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 weak muscle groups characteristically leads to improvement in strength of those muscles. Additional tests are often performed, as mentioned below. Furthermore, a good response to medication can also be considered a sign of autoimmune pathology.

Physical examination

Muscle fatigability can be tested for many muscles.^[7] A thorough investigation includes:

• looking upward and sidewards for 30 seconds: ptosis and diplopia.
• looking at the feet while lying on the back for 60 seconds
• keeping the arms stretched forward for 60 seconds
• 10 deep knee bends
• walking 30 steps on both the toes and the heels
• 5 situps, lying down and sitting up completely
• "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show^[3]

Blood tests

If the diagnosis is suspected, serology can be performed in a blood test to identify certain antibodies:

• One test is for antibodies against the acetylcholine receptor.^[3] 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.

• A proportion of the patients without antibodies against the acetylcholine receptor have antibodies against the MuSK protein.^[8]

• In specific situations (decreased reflexes which increase on facilitation, co-existing autonomic features, suspected presence of neoplasm, especially of the lung, presence of increment or facilitation on repetitive EMG testing) testing is performed for Lambert-Eaton syndrome, in which other antibodies (against a voltage-gated calcium channel) can be found.

Neurophysiology

Muscle fibers of patients with MG 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 MG,^[3] 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 (i.e. their 'jitter'), the diagnosis can be made.

Edrophonium test

Photograph of the patient showing right partial ptosis. The left lid shows compensatory pseudo lid retraction because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation). b. After an edrophonium test: Note the improvement in ptosis.

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, Reversol) or neostigmine (Prostigmin), drugs that block 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.^[9]

Imaging

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

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 sensitive ways to identify thymomas, and are generally done for this reason.^[10]

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. The forced vital capacity may be monitored at intervals in order not to miss a gradual worsening of muscular weakness. Severe myasthenia may cause respiratory failure due to exhaustion of the respiratory muscles.^[11]

Pathological findings

Muscle biopsy is only performed if the diagnosis is in doubt and a muscular condition is suspected. Immunofluorescence shows IgG antibodies on the neuromuscular junction. (Note that it is not the antibody which causes myasthenia gravis that fluoresces, but rather a secondary antibody directed against it.) Muscle electron microscopy shows receptor infolding and loss of the tips of the folds, together with widening of the synaptic clefts. Both these techniques are currently used for research rather than diagnostically.^[6]

Associations

Myasthenia Gravis is associated with various autoimmune diseases^[12], including:

• Thyroid diseases, including Hashimoto's thyroiditis and Graves' disease
• Diabetes mellitus type 1
• Rheumatoid arthritis
• Lupus, and
• Demyelinating CNS diseases

Seropositive and "double-seronegative" patients often have thymoma or thymic hyperplasia. However, anti-MuSK positive patients do not have evidence of thymus pathology.

In pregnancy

In the long term, pregnancy does not affect myasthenia gravis. Up to 10% of infants with parents affected by the condition are born with transient (periodic) neonatal myasthenia (TNM) which generally produces feeding and respiratory difficulties.^[13] TNM usually presents as poor sucking and generalized hypotonia (low muscle tone). Other reported symptoms include a weak cry, facial diplegia (paralysis of one part of the body) or paresis (impaired or lack of movement) and mild respiratory distress. A child with TNM typically responds very well to acetylcholinesterase inhibitors. The mothers themselves suffer from exasperated myasthenia in a third of cases and for those who it does worsen, it usually occurs in the first trimester of pregnancy. Signs and symptoms in pregnant mothers tend to improve during the second and third trimester. Complete remission can occur in some mothers.^[14] Immunosuppressive therapy should be maintained throughout pregnancy as this reduces the chance of neonatal muscle weakness, as well as controlling the mother's myasthenia.^[13]

Very rarely, an infant can be born with arthrogryposis multiplex congenita, secondary to profound intrauterine weakness. This is due to maternal antibodies that target an infant's acetylcholine receptors. In some cases, the mother remains asymptomatic.^[13]

Treatment

Treatment is by medication and/or surgery. Medication consists mainly of cholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process. Thymectomy is a surgical method to treat MG. For emergency treatment, plasmapheresis or IVIG can be used as a temporary measure to remove antibodies from the blood circulation.

Medication

Neostigmine, chemical structure.

• Acetylcholinesterase inhibitors: neostigmine and pyridostigmine can improve muscle function by slowing the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor. Usually doctors will start with a low dose, eg 3x20mg pyridostigmine, and increase until the desired result is achieved. If taken 30 minutes before a meal, symptoms will be mild during eating. Side effects, like perspiration and diarrhea can be countered by adding atropine. Pyridostigmine is a short-lived drug with a half-life of about 4 hours.

Azathioprine, chemical structure.

• Immunosuppressive drugs: prednisone, cyclosporine, mycophenolate mofetil and azathioprine may be used. It is common for patients to be treated with a combination of these drugs with a cholinesterase inhibitor. Treatments with some immunosuppressives take weeks to months before effects are noticed. Other immunomodulating substances, like drugs preventing acetylcholine receptor modulation by the immune system are currently being researched^[15]

Plasmapheresis and IVIG

If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the putative antibody from the circulation. Also, Intravenous immunoglobulins (IVIG) can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits, typically measured in weeks.^[16]

Surgery

Main article: thymectomy

Thymectomy, the surgical removal of the thymus, is essential in cases of thymoma in view of the potential neoplastic effects of the tumor. However, the procedure is more controversial in patients who do not show thymic abnormalities. Although some of these patients improve following thymectomy, some patients experience severe exacerbations and the highly controversial concept of "therapeutic thymectomy" for patients with thymus hyperplasia is disputed by many experts and efforts are underway to unequivocally answer this important question.

There are a number of surgical approaches to the removal of the thymus gland: transsternal (through the sternum, or breast bone), transcervical (through a small neck incision), and transthoracic (through one or both sides of the chest). The transsternal approach is most common and uses the same length-wise incision through the sternum (breast bone)used for most open-heart surgery. The transcervical approach is a less invasive procedure that allows for removal of the entire thymus gland through a small neck incision. There has been no difference in success in symptom improvement between the transsternal approach and the minimally invasive transcervical approach.^[17] However for patients with a thymoma it is important that all the tissue is removed as thymic tissue can regrow. Thymomas can be malignant and are thought to be the onset of other diseases as well. For this reason, many surgeons will only recommend the full sternotomy approach to a thymectomy.

Thymoma is relatively rare in younger (<40) patients, but paradoxically especially younger patients with generalized MG without thymoma benefit from thymectomy. Of course, resection is also indicated for those with a thymoma, but it is less likely to improve the MG symptoms.

Prognosis

With treatment, patients have a normal life expectancy, except for those with a malignant thymoma (whose lesser life expectancy is on account of the thymoma itself and is otherwise unrelated to the myasthenia). Quality of life can vary depending on the severity and the cause. The drugs used to control MG either diminish in effectiveness over time (cholinesterase inhibitors) or cause severe side effects of their own (immunosuppressants). A small percentage (around 10%) of MG patients are found to have tumors in their thymus glands, in which case a thymectomy is a very effective treatment with long-term remission. However, most patients need treatment for the remainder of their lives, and their abilities vary greatly. It should be noted that MG is not usually a progressive disease. The symptoms may come and go, but the symptoms do not always get worse as the patient ages. For some, the symptoms decrease after a span of 3–5 years.

Epidemiology & MG in children

Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects women under 40 - and people from 50 to 70 years old of either sex, but it has been known to occur at any age. Younger patients rarely have thymoma. The prevalence in the United States is estimated at 20 cases per 100,000.^[18] Risk factors are the female gender with ages 20 – 40, familial myasthenia gravis, D-penicillamine ingestion (drug induced myasthenia), and having other autoimmune diseases.

Three types of myasthenic symptoms in children can be distinguished:^[7]

1. Neonatal: In 12% of the pregnancies with a mother with MG, she passes the antibodies to the infant through the placenta causing neonatal myasthenia gravis. The symptoms will start in the first two days and disappear within a few weeks after birth. With the mother it is not uncommon for the symptoms to even improve during pregnancy, but they might worsen after labor.
2. Congenital: Children of a healthy mother can, very rarely, develop myasthenic symptoms beginning at birth. This is called congenital myasthenic syndrome or CMS. Other than Myasthenia gravis, CMS is not caused by an autoimmune process, but due to synaptic malformation, which in turn is caused by genetic mutations. Thus, CMS is a hereditary disease. More than 11 different mutations have been identified and the inheritance pattern is typically autosomal recessive.
3. Juvenile myasthenia gravis: myasthenia occurring in childhood but after the peripartum period.

The congenital myasthenias cause muscle weakness and fatigability similar to those of MG. The symptoms of CMS usually begin within the first two years of life, although in a few forms patients can develop their first symptoms as late as the seventh decade of life. A diagnosis of CMS is suggested by the following:

• Onset of symptoms in infancy or childhood.
• Weakness which increases as muscles tire.
• A decremental EMG response, on low frequency, of the compound muscle action potential (CMAP).
• No anti-AChR or MuSK antibodies.
• No response to immunosuppressant therapy.
• Family history of symptoms which resemble CMS.

The symptoms of CMS can vary from mild to severe. It is also common for patients with the same form, even members of the same family, to be affected to differing degrees. In most forms of CMS weakness does not progress, and in some forms, the symptoms may diminish as the patient gets older. Only rarely do symptoms of CMS become worse with time.

Notable people

• Augustus Pablo, reggae musician. Died May 18, 1999 due to a collapsed lung and had suffered from the disease for some time.
• Suzanne Rogers, Emmy award winning daytime television actress; plays Maggie Horton on Days of our Lives. Diagnosed in 1984, but currently in remission; her condition was dramatized on the series as her character was shown to be suffering from it as well.
• John Spencer, World professional snooker champion 1969, 1971 and 1977. Double vision, associated with the disease, effectively ended his career in the mid 1980s.
• Vijay Tendulkar, A renowned Indian playwright; died May 19, 2008 due to complications arising out of Myasthenia gravis.
• Aristotle Onassis.
• Brandon Cox- Starting Auburn QB from 2005-2007. Finished with a record of 29-9.
• Madame Web, a fictional character from the Spider-Man comics and other media.
• Amitabh Bachchan, Bollywood superstar, Star of Millennium (voted on BBC).
• Christopher Robin Milne, 1920-1996, of Winnie-the-Pooh fame and son of author A.A. Milne.
• Mary Broadfoot Walker, British physician who first discovered the effectiveness of physostigmine in the treatment of myasthenia gravis.

References

1. ^ ^{a b} Conti-Fine BM, Milani M, Kaminski HJ (2006). "Myasthenia gravis: past, present, and future". J. Clin. Invest. 116 (11): 2843–54. doi:10.1172/JCI29894. PMID 17080188. 
2. ^ Jaretzki A, Barohn RJ, Ernstoff RM, et al. (2000). "Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America". Neurology 55 (1): 16–23. PMID 10891897. http://www.neurology.org/cgi/content/full/55/1/16. 
3. ^ ^{a b c d e} Scherer K, Bedlack RS, Simel DL. (2005). "Does this patient have myasthenia gravis?". JAMA 293 (15): 1906–14. doi:10.1001/jama.293.15.1906. PMID 15840866. 
4. ^ Bedlack RS, Sanders DB. (2000). "How to handle myasthenic crisis. Essential steps in patient care.". Postgrad Med 107 (4): 211–4, 220–2. PMID 10778421. http://www.postgradmed.com/issues/2000/04_00/bedlack.htm. 
5. ^ Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science (1973) 180:871–2.
6. ^ ^{a b} Losen M, Stassen MH, Martínez-Martínez P, et al. (2005). "Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis". Brain 128: 2327–37. doi:10.1093/brain/awh612. PMID 16150851. 
7. ^ ^{a b} Baets, M.H.; H.J.G.H. Oosterhuis (1993). Myasthenia gravis. DRD Press. pp. 158. ISBN 3805547366. 
8. ^ Leite MI, Jacob S, Viegas S, et al. (July 2008). "IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis". Brain 131 (Pt 7): 1940–52. doi:10.1093/brain/awn092. PMID 18515870. PMC: 2442426. http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18515870. 
9. ^ Seybold ME (1986). "The office Tensilon test for ocular myasthenia gravis". Arch Neurol 43: 842–3. PMID 3729766. 
10. ^ de Kraker M, Kluin J, Renken N, Maat AP, Bogers AJ (2005). "CT and myasthenia gravis: correlation between mediastinal imaging and histopathological findings". Interact Cardiovasc Thorac Surg 4: 267–71. doi:10.1510/icvts.2004.097246. PMID 17670406. 
11. ^ Thieben MJ, Blacker DJ, Liu PY, Harper CM Jr, Wijdicks EF (2005). "Pulmonary function tests and blood gases in worsening myasthenia gravis". Muscle Nerve 32: 664–667. doi:10.1002/mus.20403. PMID 16025526. 
12. ^ S. Thorlacius et al., “Associated disorders in myasthenia gravis: autoimmune diseases and their relation to thymectomy,” Acta Neurologica Scandinavica 80, no. 4 (1989): 290-295.
13. ^ ^{a b c} Warrell, David A; Timothy M Cox, et al. (2003). Oxford Texbook of Medicine — Fourth Edition — Volume 3. Oxford. pp. 1170. ISBN 0-19852787-X. 
14. ^ Téllez-Zenteno JF, Hernández-Ronquillo L, Salinas V, Estanol B, da Silva O (2004). "Myasthenia gravis and pregnancy: clinical implications and neonatal outcome". BMC Musculoskeletal Disorders 5: 42. doi:10.1186/1471-2474-5-42. PMID 15546494. PMC: 534111. http://www.biomedcentral.com/1471-2474/5/42. Retrieved on 2008-07-10. 
15. ^ Losen M, Martínez-Martínez P, Phernambucq M, Schuurman J, Parren PW, DE Baets MH (2008). "Treatment of myasthenia gravis by preventing acetylcholine receptor modulation". Ann N Y Acad Sci 1132: 174–9. doi:10.1196/annals.1405.034. PMID 18567867. 
16. ^ Juel VC. (2004). "Myasthenia gravis: management of myasthenic crisis and perioperative care.". Semin Neurol 24 (1): 75–81. doi:10.1055/s-2004-829595. PMID 15229794. 
17. ^ Calhoun R, et al. (1999). "Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients.". Annals of Surgery 230 (4): 555–561. doi:10.1097/00000658-199910000-00011. PMID 10522725. 
18. ^ "What is Myasthenia Gravis (MG)?". Myasthenia Gravis Foundation of America. http://www.myasthenia.org/amg_whatismg.cfm. 

External links

• The Myasthenia Gravis Foundation of America
• The Myasthenia Gravis Association (MGA) in the United Kingdom & the Republic of Ireland
• The Myasthenia Gravis Coalition of Canada

v • d • e Diseases of myoneural junction and muscle / neuromuscular disease (G70-G73, 358-359) Neuromuscular- junction disease autoimmune (Myasthenia gravis, Lambert-Eaton myasthenic syndrome) Myopathy Muscular dystrophy (DAPC) AD Limb-girdle muscular dystrophy 1 · Oculopharyngeal · Facioscapulohumeral · Myotonic · Distal (most) AR Limb-girdle muscular dystrophy 2 · Congenital (Fukuyama, Ullrich) XR dystrophin (Becker's, Duchenne) · Emerin Emery-Dreifuss Channelopathy Myotonia Myotonia congenita · Thomsen disease · Neuromyotonia/Isaacs syndrome · Paramyotonia congenita Periodic paralysis Hypokalemic · Hyperkalemic Congenital myopathy Bethlem myopathy · Central core disease · Centronuclear myopathy · Nemaline myopathy · Zaspopathy Mitochondrial myopathy MELAS · MERRF · KSS · PEO Other Inflammatory myopathy

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