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Guide to MG |
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Guide to MG, Printable Version
John C. Keesey, M.D. and Rena Sonshine The following summary has been prepared to provide information written in lay language about myasthenia gravis (MG). This is not "the official version," but just a personal view of a complicated and sometimes controversial subject. Each person's experience with it is in some way unique, and this guide can approach the topic only in a general way. You can order a copy of this article from MGFI, see MG Brochures.
The distinctive feature of MG is fluctuating weakness of muscles, made worse by use of those muscles and improved at least partially by rest of the same muscles. The muscles affected are called voluntary or striated muscles. Involuntary heart muscle and smooth muscles of the gut, blood vessels, and uterus are not involved in MG. Muscles which we use all the time, such as the six muscles which move each eyeball and those which hold the eyelids open, are often but not always involved. The muscles of facial expression, smiling, chewing, talking, or swallowing can be selectively affected in some people with MG. We take these muscles for granted until they don't work! Other muscles which may be affected include those of the neck and limbs. Although MG is said to be painless, pain in the back of the neck and head may be present if neck muscles which hold up the head are weak and in spasm. Symmetrical limb weakness occurs in many other nerve and muscle diseases, but in MG, limb weakness is often not symmetrical, one side being weaker than the other. Shoulder weakness is demonstrated by trouble holding up an arm to comb or shampoo one's hair, or to shave or put on make-up. The grip may become weak opening jars (and child-proof medicine bottles), hips may be weak getting out of deep chairs or the bathtub, and legs may tire climbing stairs or when walking distances. The "gravis" or seriousness of myasthenia is particularly noticeable when muscles we use in breathing are affected. If breathing or coughing becomes insufficient, the patient is said to be in crisis, and mechanical breathing assistance in a hospital may be necessary. It is seldom useful to try to determine whether the respiratory insufficiency is a "myasthenic crisis" (weakness from MG exacerbation) or a "cholinergic crisis" (weakness from too much anticholinesterase medication), because most crises have multiple causes and the treatment for any crisis is respiratory assistance. Patients with trouble swallowing and talking are the ones most likely to have trouble breathing also, and usually before a crisis happens there are progressive warning signs that swallowing, talking, and breathing are becoming compromised. Different muscle groups are affected in different patients with MG. Some have only ocular myasthenia involving the eye muscles and eyelids; others have mainly swallowing difficulties or slurred speech; others have generalized MG affecting many muscle groups. Even though specific muscle fatigue is the hallmark of MG, patients with MG do not often complain of non-specific or general fatigue. Skin sensation is normal. MG remains confined to the eye muscles in about 15% of patients who initially present with only ocular myasthenia. Within the first year after onset about half of the ocular MG patients will go on to experience involvement of other muscles, and another 30% do so during the next two years. The maximum extent of involvement in an
individual patient usually manifests itself within the first 5 to
7 years, and thereafter it tends not to be progressive, even
though muscle involvement and severity of weakness may still
fluctuate from hour-to-hour and day-to-day. The typical untreated
patient may feel strong on awakening from a night's rest or a nap,
but experiences increasing muscle fatigue as the day progresses
Although MG can be fatal if a respiratory crisis is not
immediately treated, normal life expectancy MG occurs throughout the world and in all ethnic groups. Its onset can occur at any age from birth to the ninth decade, although women usually notice it first in the childbearing ages and men in middle age. Rarely, infants born to non-myasthenic mothers have myasthenic symptoms on the basis of a genetic defect in neuromuscular transmission. These infants are said to have congenital myasthenia. However, the vast majority of MG cases are autoimmune, in which the body's immune system mistakenly attacks and destroys special proteins located on the muscle surface where the nerve attaches to the muscle. These proteins respond to the chemical acetylcholine which is released by the stimulated nerve, and this response starts the process which causes the muscle to contract. These special proteins are called acetylcholine receptors. No one knows what sets off the autoimmune reaction, but if some acetylcholine receptors are missing because of it, the response of the muscle to nerve impulses is poor and weakness may occur. Twelve percent of babies born to mothers with autoimmune MG develop a feeble cry, poor sucking, respiratory distress and "floppiness" which I can be reversed by anticholinesterase medication or blood exchange. These signs of neonatal myasthenia spontaneously disappear over the first few months of life, and no well-documented case exists of autoimmune MG occurring in a child of a mother with autoimmune MG. Autoimmune diseases such as MG, thyroid disease,
lupus, rheumatoid arthritis and juvenile diabetes seem to run in
families, and these families statistically (but not invariably)
share certain tissue markers. New and promising experimental
treatments for autoimmune diseases are based upon the presence of
such markers. HOW IS THE DIAGNOSIS OF MG CONFIRMED? Weakness and fatigue are such common complaints from a variety of causes that it is not surprising that the diagnosis of myasthenia gravis is often missed in people in whom the weakness is mild or restricted to only a few muscles. Once the possibility occurs to a doctor, however, there are several approaches to confirming the diagnosis. One way is to test for specific muscle fatigue by repetitive movements of the eyes, arms or legs. This can be done without equipment, or it can be done electrically by recording a weakening muscle response when a nerve to that muscle is electrically stimulated repetitively. Not every person with the disease will show a characteristic response to this repetitive nerve stimulation. A much more sensitive electrical test called single fiber electromyography is more likely to show evidence of neuromuscular malfunction (not specific for MG), but it requires special equipment and skills which are not widely available. A very specific test for MG is a blood test to look for serum antibodies to acetylcholine receptor. Eighty percent of all patients with MG have abnormally elevated serum levels of these antibodies, but positive test results are less likely in patients with mild or purely ocular forms. The chance of receiving a falsely positive test result from a reputable laboratory is small, although borderline tests should be repeated. A third approach to MG diagnosis is pharmacological, using drugs which may worsen or improve the weakness. At one time the native South American poison curare was used in very small doses to test for worsening of MG, but this can be dangerous and has fallen out of fashion. Nowadays the short-acting drug edrophonium chloride (brand-name "Tensilon") is used intravenously to try to make the diagnosis of MG by reversing some obvious and measurable weakness, such as a drooping eyelid or a low breathing capacity. Sometimes all these tests are negative or
equivocal in someone whose story and examination still seem to
point to a diagnosis of myasthenia gravis. The positive clinical
findings should probably take precedence over negative
confirmatory tests, each of which has its weaknesses. Some people,
therefore, have to be followed by their doctors with a diagnosis
of "possible MG" or "probable MG" until the situation clarifies
itself. Under
such circumstances both the patient and the doctor have to keep an
open mind. A lot of common-sense things can be very effective in coping with MG. Plenty of rest and a well balanced diet actually help reverse the weakness. Preference should be given to foods high in potassium, such as oranges, tomatoes, apricots and their juices, bananas, broccoli and white meat of fowl. If possible, one should try to avoid exposure to infections and all forms of stress, but of course that's easier said than done. It is very important that patients try to pace their activities so that they don't fatigue themselves unnecessarily. This may mean resting the eyes by closing them for a few minutes each hour or lying down briefly several times during the day. Each patient is different and by experience can adopt a daily schedule which optimizes the good times and minimizes the weak times. Support groups of MG patients offer many practical ideas for coping with this condition. Avoid Exacerbations Many things can exacerbate myasthenic weakness temporarily, including infections (such as a cold, pneumonia, or even a tooth abscess), fever, excessive heat or cold, over-exertion, and emotional stress. Some women notice increasing severity of their MG during a particular time of the menstrual cycle, during pregnancy, or after delivery. Either too little or too much thyroid activity can worsen MG, as can too little potassium in the body, such as is brought on by diuretics or frequent vomiting. The stress of surgery or radiation therapy can make MG temporarily worse. The effect of pregnancy on MG follows the "one-third rule": One-third of pregnant myasthenics get better and one-third get worse at some time during their pregnancy, while one-third do not change. The course of MG during previous pregnancies does not predict the course of subsequent pregnancies. MG frequently manifests itself for the first time during a pregnancy. Standard drugs used to treat MG such as anticholinesterase medications or prednisone (see below) are not associated with significant risk for congenital defects, and plasmapheresis (see below) has been carried out safely during pregnancy. Obstetrical problems with myasthenics are uncommon because the uterus, a smooth muscle, is unaffected in myasthenia. Only during the second stage of labor when voluntary "striated" abdominal muscles are used does myasthenic weakness become noticeable. Even many non-myasthenic woman notice increased weakness after delivery, and this may be exaggerated in MG. People with MG should make sure that their doctors and dentist are aware that many drugs can adversely affect some people with MG. The most common offenders are the very medications used to treat MG (too much anticholinesterase, steroids, or thyroid medication; see below), but anesthetic agents, muscle relaxants, magnesium salts, anticonvulsants and other membrane stabilizers for irregular heart rate, as well as amino-glycoside antibiotics, are other drugs generally accepted to unmask or exacerbate MG. The Table on pages 8 and 9 includes drugs which have been reported in medical journals to cause weakness in humans. Common sense dictates that sometimes an irregular heart beat, for instance, or a severe infection sensitive only to one of the antibiotics on the list will take precedence over the MG, and one of these drugs will have to be used, cautiously. A medical alert bracelet can alert medical personnel to use drug precautions in case of an accident or crisis. In addition to the above common-sense approaches towards improving health and avoiding trouble, there are some well-known medications and newer treatments which can be tried to counteract the bothersome symptoms of MG. Anticholinesterases, which boost the body's
neuromuscular transmitter acetylcholine by blocking the enzyme
which usually breaks it down, include neostigmine (brand-name,
Prostigmin") and pyridostigmine (brand-name, "Mestinon"). Another
drug in this category, ambenonium chloride (brand-name "Mytelase"),
is used much less frequently. These medicines don't do anything to
cure MG, but they can provide a temporary crutch Because muscle involvement and severity vary so much among patients with MG, there is no fixed dose or time schedule for anticholinesterases. For infants and children the dose is based on body weight, starting at one milligram per kilogram for "Mestinon" and 0.3 milligrams per kilogram for "Prostigmin." Generally it is a good idea to try to keep the adult dose somewhere between 1/2 and 2 of the 60 milligram tablets of "Mestinon" or a similar amount of the 15 milligram tablets of "Prostigmin," and to take the medication no closer than every three hours, always keeping on the low side to avoid tolerance (the drug may become less effective with time) or overdosing. These medications produce their maximal effects (good and bad) about one to two hours after ingestion, and these effects wear off after about three hours or sometimes longer. Therefore, patients who have trouble chewing or swallowing are advised to take their medication at a time which will produce optimal strength during meals. These medicines can cause stomach cramps and gut hyperactivity, so they should be taken with bland food such as crackers or milk to minimize these problems. Increased perspiration, salivation, muscle twitching and muscle cramps are other unpleasant side effects sometimes experienced with this type pf medication. The presence of these symptoms maybe an indication of taking too much medication, in which case Mestinon should be taken at longer intervals or in lesser amounts. "Mestinon" also comes as an 180 milligram "Mestinon Timespan" in which 60 milligrams is released immediately and the remaining 120 milligrams are released over several hours. Timespan is used for patients who require medication throughout the night, but the uneven release by Mestinon Timespan provides less predictable results than with ordinary Mestinon. There is also a liquid "Mestinon" syrup for children and adults who have trouble swallowing pills. Historically, the drug ephedrine sulfate was discovered to improve myasthenic weakness a decade before the use of anticholinesterases, and it may still come in handy as an auxiliary medication, added to anticholinesterases, for those MG patients who need a little extra strength and are not bothered by its possible side effects of nervousness, palpitations or insomnia. It is taken as 25 milligram capsules two or three times a day. Plasmapheresis (the drawing off of plasma) is an expensive short-term treatment in which several liters of blood are removed from the patient's vein, spun in a centrifuge, and the red blood cells are returned intravenously in artificial plasma (albumin and saline solution). Plasmapheresis is used repetitively (every other day) for two weeks when short-term benefit is critical to the patient, such as in impending respiratory crisis or prior to surgery or irradiation. Some patients get stronger several days following this procedure, but the benefit lasts only weeks. Another expensive short-term treatment, intravenous human immune globulin or IVIG, may be thought of as the opposite of plasmapheresis. Instead of drawing off the offending antibodies, IVIG swamps the body with pooled gamma globulin antibodies from many donors. HIV and hepatitis viruses are removed completely during the preparation of IVIG. IVIG is thought to have a nonspecific suppressive effect upon the immune system. Like plasmapheresis, the beneficial effects if they occur last only weeks in MG patients. Therefore, its appropriate use at the present time is to avoid or curtail a stay in the even more expensive intensive care unit of a hospital. Allergic reactions sometimes occur, so the first treatment should be given in a hospital or doctor's office. Plenty of fluids should accompany the treatments to minimize the severe headache which can occur. Usually the short-term treatments above do not completely relieve the symptoms of MG even temporarily, and eventually the patient with more than just mild disease must discuss with her/his doctor the controversial aspects of what to do next to attempt to obtain a long-term remission. This is especially true for patients with serious trouble swallowing or breathing, for whom long-term treatments may protect against rapid deterioration of these functions. One approach is to do nothing more, and hope to be one of up to 20% of MG patients who go into a natural, spontaneous remission which lasts longer than one year. No one knows why MG fluctuates or why natural remissions occur. Without spontaneous remission, the patient seeking more lasting improvement of generalized MG is faced with two choices: (A) Major thoracic surgery (thymectomy), or (B) Potentially dangerous drugs. Each approach has advantages and disadvantages. (A) Thymectomy: About 15% of patients with MG
are found by chest x-ray, computed tomography (CT), or magnetic
resonance imaging (MRI) of the chest to have a tumor of the thymus
gland called a thymoma. Although most thymomas are benign, they
are usually removed surgically because of a perceived potential
for malignancy. This has led to thymectomy as well for MG patients
without thymoma. If most of the thymus gland is removed at
surgery, myasthenic symptoms usually lessen and in some
individuals go The thymus gland is an organ involved in the development of the immune system. It migrates from the neck into the chest during formation of the fetus, and in adults it lies beneath the breastbone (sternum). Like tonsils and adenoids, the thymus is large in infants and gets smaller, to be replaced by fat, as we get older. The thymus gland is not enlarged in patients with myasthenia, but often under the microscope it contains more cells than normal (the pathology term is "hyperplasia"), especially if myasthenia has been present several years. Some neurologists do not think thymectomy adds to other treatments for MG, but most neurologists recommend it for some patients. In the past, thymectomy was not performed on patients who were over 25 years old (or, more recently, over 45 years old), nor was it offered to MG patients who have had their disease for more than five years. Yet some older patients and some long-standing MG patients have benefited from thymectomy, so now the recommendation for this procedure has to be considered on an individual basis. Another question regarding thymectomy is, "Which surgical technique is best"? Most surgeons split the breastbone in a transsternal thymectomy, but a few surgical groups have championed a less traumatic approach through the neck, called a transcervical thymectomy. A patient who wants to shop around the country can find practically any surgical gradation between these two techniques, or even (at Columbia University in New York City) both a transsternal and a transcervical thymectomy on the same MG patient. The results of this double approach are good, but so far not really better than a careful removal of all discernible thymic tissue through a transsternal approach. About 30% of MG patients without a thymoma who undergo thymectomy eventually go into complete drug-free remission and another 50% experience marked improvement. This improvement usually does not occur immediately after surgery, but may take up to several months or years to reach its peak effect. We are unable to predict beforehand who will benefit from thymectomy, and even after benefit occurs there is still a small possibility of subsequent relapse. However, thymectomy itself rarely worsens the long-term course of MG. Even invasive thymomas are not always detected
with imaging tests and have been discovered serendipitously during
thymectomy surgery. Such experiences would argue in favor of
eventual thymectomy over immunosuppressive drug therapy in
otherwise healthy young or middle-aged MG patients, once the
patient is up to the surgery. (B) Immunosuppressive Drug Therapy: These drug alternatives consist of a group of general suppressants of the body's immune system, although no one really knows how they work in MG. In decreasing order of their frequency of use in MG, they are prednisone, azathioprine ("Imuran"), cyclophosphamide ("Cytoxan") and cyclosporine ("Sandimmune"). Except for prednisone, none of these drugs is endorsed by its manufacturer specifically for treatment of MG. Prednisone is a synthetic drug taken by mouth
which resembles natural hormones produced by the cortex of human
adrenal glands. The body depends upon these hormones, called
corticosteroids or "steroids," during stress. When prednisone is
taken in doses higher that 20 milligrams daily for longer than a
week, the body's natural production of adrenal hormones begins to
decrease. This is called "adrenal suppression," and is an
undesirable but inevitable effect of taking high doses of a
synthetic steroid. Once this occurs, prednisone cannot be stopped
all at once but must be slowly tapered down over several months to
give the adrenal glands a chance to "wake up" and begin producing
natural adrenal hormones again. Some physicians try to avoid this initial weakening by starting with a low dose of prednisone and gradually working up to a recommended amount of 50 to 60 milligrams every day for several months. Onset of improvement in muscle strength usually occurs within 2 weeks but may take as long as 2 months. In order to lessen the chance of undesirable effects, a gradual transition to alternate-day therapy is made after about two months of daily therapy, so that eventually twice the usual dose is given every other day for several more months. As soon as is feasible (3 to 12 months), the drug is very slowly tapered over many months to a long-term maintenance dosage (ideally, 5 to 10 milligrams every other day) sufficient enough to keep myasthenic symptoms in abeyance. The choice of prednisone therapy is thus a long-term commitment lasting several years. Thirty percent of MG patients on high-dose prednisone therapy experience a drug-dependent symptom-free remission, and another 50% obtain marked improvement on prednisone. One out of four MG patients also experiences serious complications from this drug. Patients on prednisone should watch their weight, keep as active as possible, eat a balanced diet (high in protein, calcium and potassium but low in salt, free sugar and fat), stay out of crowds in enclosed areas in order to avoid people with infections, and see their physicians regularly. Azathioprine (brand-name Imuran) was used to treat MG in Europe for years, but U S experience is relatively recent, since it was introduced as an accompaniment to plasmapheresis. It is being used mainly for patients who cannot tolerate or do not respond to prednisone, or as an aid to decreasing the dosage of prednisone which a patient requires. The undesirable effects of azathioprine are less varied than those of prednisone but they can be very serious. Young women who may want to have children should avoid this drug, because it has a known potential for producing fetal deformities. Complete blood counts must be obtained periodically at the beginning of azathioprine therapy to detect rapid drops in the number of white and red cells in the blood, and periodic liver function tests must also be obtained to detect potent toxicity to the liver. Sometimes a systemic reaction occurs in the first few weeks of azathioprine therapy, consisting of fever, nausea, vomiting, loss of appetite, and abdominal pain. The drug must then be discontinued. While most of the undesirable effects of azathioprine make themselves known early on, the beneficial effects seem to take months to occur and often emerge so slowly and subtly that they are apparent only in retrospect. Remissions which occur on azathioprine, like prednisone, are drug-dependent, and symptoms of MG recur when the drug is discontinued. There is still much to learn about azathioprine, including answers to such worrisome questions as whether it may increase the risk for cancer many years later. Cyclophosphamide (brand-name Cytoxan) is considered only for the most severe cases of MG when other therapies have failed. Hair loss is an almost universal occurrence on the drug, and the risk of bladder hemorrhage and bladder cancer are of great concern. However, experience from the Philippines reported complete drug-free remission for a year and a half in three out of four MG patients who were treated with cyclophosphamide. Experimental regimens in which cyclophosphamide is given intravenously or orally once a week-instead of daily-may reduce the occurrence of adverse effects. This drug usually requires the assistance of a rheumatologist or oncologist who is more familiar with it than are most neurologists. Cyclosporine (brand-name Sandimmune) has
recently been tested in clinical trials at Although cyclosporine is currently the gold standard for evaluating several new immunosuppressive agents, current pharmacologic approaches to nonspecific immune suppression of MG leave much to be desired. It is hoped that future treatment strategies will employ more specific regulation of immunity focused on selected molecules or cells, approaches which are at present experimental. There is still much to learn about myasthenia gravis, its diagnosis and its treatment. There is no one recipe for all situations, so the choice of treatment for an individual patient requires judgment and experience. Patients and their doctors are often required to make decisions even when the evidence is inconclusive. Patients need all the support which doctors, family and friends can offer. Acknowledgments:
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