Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (41 page)
While muscle weakness is a primary symptom of MG, it’s not specific to myasthenia gravis. Again, muscle problems, especially around the eyes, can be caused by congenital myasthenia syndrome or Hashimoto’s thyroiditis or Graves’ disease, and medications may produce or exacerbate muscle weakness. So other causes must be definitively ruled out.
“A good clinical evaluation with a thorough history is really at the heart of making a diagnosis of myasthenia. Lab tests can be useful, but are not as useful as a good clinical evaluation,” stresses Dr. Massey.
Among the tests that can help confirm a diagnosis is a test for antibodies to the acetylcholine receptor and tests that involve electrically stimulating muscle fibers, either a single muscle fiber or repetitively stimulating specific groups of muscle fibers. “We may have to do other routine electrophysiological studies to verify key abnormalities we see on these tests, or to make sure there’s no other underlying problem causing the muscle weakness,” explains Dr. Massey.
Acetylcholine receptor (AChR) antibodies
are among several types of antibodies are found in the majority of patients with myasthenia gravis. More than three-quarters of people with generalized MG and around half of those with ocular MG have antibodies directed against the acetylcholine receptor.
But unlike some markers of inflammation, the serum concentration of
anti-AChR antibodies
is not associated with the severity of disease (antibody levels can be low at the onset of MG and increase later on). AChR antibodies are also increased in women with lupus,
inflammatory neuropathy
,
amyotrophic lateral sclerosis (ALS)
,
thymoma
, in women with rheumatoid arthritis taking D-penicillamine, and even in healthy relatives of MG patients. You can even have a false-positive test if blood is drawn within 48 hours of a surgical procedure involving general anesthesia and muscle relaxants. But generally, elevated AChR antibodies—together with key clinical symptoms—confirm the diagnosis of myasthenia gravis, says Dr. Massey.
Anti-striational muscle antibodies (StrAbs)
react with the contractile parts of skeletal muscle tissue. StrAbs are found in up to half of MG patients who test negative for AChR antibodies, as well as in older patients and in people with more severe MG. However, since StrAbs are rarely elevated in people who do not have AChR antibodies, the test is not useful for confirming a diagnosis of MG.
The test is useful in detecting and predicting thymomas. StrAbs are found in more than 90 percent of MG patients with thymomas (and in a third of people who have thymomas but don’t have MG). Over half of people with an early onset of MG (before age 50) and thymomas also have elevated StrAbs.
Antibodies to muscle-specific receptor tyrosine kinase (MuSK)
are found in up to half of people who test negative for AChR antibodies. MuSK is a protein essential in the development of the neuromuscular junction. Recent data suggests patterns of weakness in MG and the response to certain treatments may be different in people with MuSK antibodies.
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Ten percent of people with MG do not have detectable serum antibodies to either AChR or MuSK. In these “seronegative” patients, the diagnosis is based on their response to electrodiagnostic testing and cholinesterase inhibitors like Tensilon (see below).
Elevated AChR and MuSK antibodies can confirm a diagnosis of myasthenia gravis.
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Electromyography repetitive nerve stimulation (RNS)
uses a harmless, low-frequency electrical signal to stimulate nerves, and the reaction in muscle is measured. In people with myasthenia, the muscle response becomes progressively weaker with each stimulation. Multiple muscle groups may be tested. This decreasing response is seen more often in facial muscles, arm muscles (
biceps, deltoids
), and shoulder muscles (
trapezius
). A significant decrease in response to repetitive stimulation in either a hand or shoulder muscle is found in about 60 percent of patients with myasthenia gravis. The response is not specific to MG, but an abnormal finding is a good predictor of the disease.
Single-fiber EMG (SFEMG)
involves recordings that can be made from pairs of muscle fibers supplied by branches of a single nerve fiber. It’s time consuming and difficult, and requires special expertise and equipment, but is the most sensitive diagnostic test of neuromuscular transmission abnormalities. However, in rare instances, it may not be specific for MG. What’s seen is a “jitter” in some muscles in almost all patients with myasthenia gravis. Patients with mild or purely ocular muscle weakness may have increased “jitter” only in facial muscles.
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The test is sensitive for MG in greater than 90 percent of cases.
The
edrophonium challenge test
is done if electrophysiological studies prove inconclusive or a patient has coexisting problems that may complicate her case. The test uses an intravenous infusion of a chemical called
edrophonium chloride (Tensilon)
to temporarily slow the breakdown of acetylcholine. Tensilon takes effect rapidly, in a minute or less, improving muscle weakness (such as ptosis) if it’s caused by the abnormal neuromuscular transmission that occurs in MG. Tensilon’s effects last only 5 to 10 minutes. If you have ptosis, and after the injection the ptosis goes away, that’s a fairly good indication that you may have MG.
A small test dose is usually given to make sure there’s no unusual sensitivity or side effects, such as a slowed heartbeat (a dose of atropine is kept on hand to counteract its effects). The test cannot be given to people with heart problems or the elderly.
The edrophonium test is not completely specific for MG; patients with other conditions may also show a response.
A similar drug,
neostigmine
, can be given as an intramuscular injection. Neostigmine takes effect more slowly and lasts longer, but has less potential for side effects. In some people, a trial of the drug
pyridostigmine (Mestinon)
may produce improvement in muscle weakness that can’t be seen after only one dose of edrophonium chloride or neostigmine.
Because thyroid disease occurs so often with MG, thyroid function tests are needed to rule out Graves’ disease, hyperthyroidism, or hypothyroidism as a cause of muscle weakness. These tests may include thyroid stimulating hormone (TSH) and thyroid antibody tests.
A CT scan of the chest is also needed to examine the thymus, since many women may have thymomas or thymus abnormalities.
Jackie’s story continues:
I was diagnosed with pernicious anemia two years before I found out I had MG; I was told I had rheumatoid arthritis around the same time I was diagnosed with MG, in December. And over the years I had several falls and injured myself, and now we look back and almost all of it was clumsy behavior. So 1 probably had myasthenia for a long time, and probably these other illnesses, too. Now every six months I get tested with bloodwork for thyroid.
Myasthenia gravis appears to affect more women than men at any age, particularly in their twenties and thirties. During the sixties and seventies the incidence among men increases from that seen in middle age. But things may not be that clear-cut.
“Presumably there’s some hormonal relationship, but what that relationship may be is unknown. Some of the more recent statistics, especially with the aging of the population, give a more equal ratio between men and women after age 50,” remarks Dr. Massey. As the over-50 population has increased, so has the prevalence of MG and the average age at diagnosis. As far as it’s known, there are no sex differences in what occurs in the thymus or in the presentation of the disease, she adds. There may be some ethnic differences in the disease.
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However, gender does play a role in the way MG is treated, mostly in the choice of medications for women of childbearing age.
Because myasthenia gravis can be so varied and differs in each person, treatment is highly individualized according to the severity of disease, age, sex, and the degree of functional impairment. The major difficulty in treating MG is that a response may be difficult to measure; symptoms can improve spontaneously, or the disease can go into remission, especially early on.
For the majority of women with MG, treatment begins with drugs that slow the breakdown of acetylcholine and relieve symptoms. The second-line treatment is removal of the thymus (
thymectomy
) or immunosuppression. Sometimes they are combined. Newer treatments can provide sustained improvement in many patients.
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Cholinesterase inhibitors
are the mainstay of treatment for symptoms of myasthenia gravis.
Anticholinesterase drugs
neutralize an enzyme that breaks down acetylcholine at the neuromuscular junction, increasing the amount of acetylcholine and giving it a better chance to be taken up by receptors, which have been reduced in number by the disease process
. Pyridostigmine bromide (Mestinon, Regonol)
and
neostigmine bromide (Prostigmin)
are the most
commonly used oral medications, and may be given in combination. Prostigmin can be given by injection
. Ambenonium (Mytelase)
may be used in moderate to severe cases.
Edrophonium chloride (Tensilon)
may also be given intravenously.
“Cholinesterase inhibitors reduce muscle weakness, but do not affect the underlying disease that causes it,” stresses Dr. Massey. “These drugs are usually given in conjunction with other treatments, particularly thymectomy in younger patients.”
Some women can show substantial improvement with cholinesterase inhibitors, while there may be little to no effect in others. The need for medication can vary from day to day (even during the same day) in response to menstruation, emotional stress, infections, and hot weather. Various muscles may even respond differently; some may get stronger, some become weaker, and others show no change at all. Muscle strength rarely returns to normal with cholinesterase inhibitors, but people can be quite functional.
The side effects are due to the drugs’ effects on receptors in smooth muscle, skeletal muscle, and certain glands. These can include: narrowing of the muscle of the iris in the eye, causing the pupil to become smaller; increased nasal and bronchial secretions; and increased salivation and urination. Gastrointestinal effects can include loose stools and diarrhea, queasiness or nausea, vomiting, and abdominal cramps. Cholinesterase inhibitors may also worsen urinary tract infections.
If you have problems with swallowing or breathing, the increased bronchial secretions and saliva can be a serious problem. If too much ACh accumulates at receptors in other muscle tissue (such as in smooth muscle), it can cause weakness and, in rare cases, respiratory failure.
Thymectomy, removal of the thymus
, increases the frequency of remissions in MG, and is recommended for most patients, especially if they have thymomas.
The current evidence (at the time of publication) suggests that thymectomy seems to be most effective in people younger than 50, particularly those with early disease, and those with moderate to severe disease who have not responded to other treatments. Improvement in symptoms may not be seen immediately; it may take place gradually over several years. Data are expected soon from an international clinical trial of thymectomy.
Some studies suggest that African Americans may have somewhat less improvement after thymectomy, but not enough to advise avoiding the surgery. “Women, particularly those who have germinal center hyperplasia in the thymus or who were diagnosed in the previous two years, tend to do better after thymectomy,” remarks Dr. Levinson.
Corticosteroid drugs
, usually
prednisone
, decrease the buildup of antibodies to acetylcholine receptors and speed up the normal death
(apoptosis
) of the cells that produce the antibodies. Corticosteroids are used to prepare patients for thymectomy, and sometimes after the surgery, in people who fail to respond completely. More than 75 percent of patients show a marked improvement, or complete relief of symptoms, with prednisone (usually in the first six to eight weeks), often followed by a total remission. Afterward, some people may be able to take prednisone every other day at lower doses.
Around one-third of patients become temporarily weaker in the first week to 10 days after starting prednisone. While treatment can be started at a low dose to minimize the problem and slowly increased until there’s improvement in muscle strength, it’s hard to predict when the worsening from prednisone may take place, and it may be confusing. People with early MG usually respond best, but 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. The major disadvantages of corticosteroid therapy are the side effects (see
pages 42
to
43
).
For women, the major concern is the development of osteoporosis, and estrogen or bone-building drugs may be needed. “The fact that prednisone accelerates bone loss is something that, on occasion, would lead me to choose another medication over prednisone,” comments Dr. Massey. “We do use bone-building drugs, such as alendronate, if there is significant osteoporosis as a complication of steroid therapy. This is something we would closely follow.”
Immunosuppressant drugs
dampen the activity of the immune system, and may be needed when a woman fails corticosteroid treatment, can’t tolerate prednisone, or is unable to take steroids.
Azathioprine (Imuran)
reverses symptoms in most women, but the effects may not be seen for four to eight months, and a woman may not achieve a full remission for one to two years. Once there’s improvement in muscle strength, it will be maintained as long as the drug is taken; if azathioprine is
discontinued, symptoms recur within two to three months. Some women may respond better to treatment with both prednisone and azathioprine than to either drug by itself. Both medications can be started simultaneously, and the dose of prednisone can be tapered once azathioprine becomes fully effective. Approximately one-third of patients have mild side effects (depending on the dose) that may require lowering their doses.
Cyclosporine A
is sometimes helpful. It mostly inhibits the T cell–dependent immune responses. Most patients will see an improvement in muscle strength within one to two months after starting cyclosporine, but maximum benefits take six months. After achieving a maximum response, the dose of cyclosporine is gradually reduced to the lowest level that will maintain symptom improvement. Adverse effects include kidney damage and high blood pressure.
Cyclophosphamide (Cytoxan)
is now used only infrequently to treat MG. It is used to treat some cancers and interferes with rapidly proliferating cells (including T cells and B cells) and reduces the production of autoantibodies. Cytoxan can be given intravenously or orally. More than half of patients become asymptomatic after one year on cyclophosphamide.
Side effects include nausea, vomiting, hair loss, appetite loss, anemia, thrombocytopenia, leukopenia, and infertility. Antinausea drugs (like
ondansetron
) given to chemotherapy patients can help relieve the nausea and vomiting. Cyclophosphamide also causes birth defects and is contraindicated in pregnancy. Infections are always a risk with any immunosuppressant drug. Life-threatening infections may occur in some people with invasive thymomas.
Mycophenolate mofetil (MMF, Cellcept)
selectively inhibits proliferation of activated B and T cells and reduces formation of autoantibodies. It was initially used to prevent rejection of organ transplants but is now used in many autoimmune diseases. MMF is typically given in combination with cyclosporine and corticosteroids and to MG patients with severe disease who don’t respond to corticosteroids and azathioprine.
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A small study presented at the 2014 Scientific Sessions of the Myasthenia Gravis Foundation of America indicated that MMF, like azathioprine, may allow corticosteroid doses to be reduced in some MG patients.
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Side effects can include an increased risk of infections and some cancers (see
page 79
).
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MMF cannot be taken during pregnancy or by women who plan to become pregnant because it can cause
birth defects and miscarriage. It can also decrease the effectiveness of oral contraceptives.
Tacrolimus (Prograf, Astagraf XL, Advagraf)
is an oral T-cell immunomodulator that dampens inflammatory cytokines.
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In MG it aids muscle contraction and strength and may enhance the effectiveness of corticosteroids. Like MMF, tacrolimus was originally approved to prevent rejection of transplanted organs and is used in other autoimmune disorders like lupus and RA.
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It is taken in capsule form, starting with a low dose of 3 mg and slowly increased to 10 mg. Common side effects can include nausea, diarrhea, and constipation. Tacrolimus can lead to high blood pressure, changes in kidney and liver function, and gastrointestinal perforation, so it needs to be carefully monitored by a physician.
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Plasma exchange (plasmapheresis)
is an exchange of the clear fluid component of the blood (plasma), which contains white blood cells and immune cells. The effect is to reduce the amount of damaging antibodies and immune complexes. Plasma exchange involves several treatments to exchange three to four liters of plasma over a two-week period. It produces rapid improvement, and is a short-term treatment for patients who experience a sudden worsening of symptoms (myasthenic “crisis”) or in those rare cases where there’s a rapid onset of disease involving the muscles of the mouth and throat (posing the threat of serious airway problems). It’s also used to quickly improve muscle strength before surgery and as an intermittent therapy for patients who don’t respond to other treatments.
Some women may improve right after the first treatment, or it may take as many as five to seven treatments to see an increase in muscle strength. Improvement can last for weeks or months, making it an effective short-term or stopgap therapy, says Dr. Massey. However, the temporary effect will be lost unless immunosuppressant drugs are given or the thymus is removed.
While most women who benefit from the initial plasma exchange will respond to subsequent exchanges, repeated treatments do not have a cumulative benefit. Plasma exchange is usually followed by thymectomy and/or immunosuppressant drugs.
Intravenous immunoglobulin (IVIG)
can be used as an alternative to plasma exchange in cases of severe myasthenic exacerbation. IVIG is usually given over a period of two to five days. It’s not clear how IVIG works; it may suppress the production of antibodies against acetylcholine receptors
(see
pages 370
to
371
). Between 50 and 100 percent of patients show improvement, usually within a week, and the effects of IVIG can last for weeks or months. However, recent studies suggest IVIG is not as effective as plasma exchange. Side effects include a “sterile” meningitis (usually manifested as a headache) or, rarely, more serious events such as
deep vein thrombosis (DVTs)
(leg clots that can fragment and travel to the heart or lungs, which can be fatal), kidney failure, heart attack, or stroke.
Jackie’s story continues:
Before I was diagnosed, I had planned to go skydiving with a group of people the next Saturday. They didn’t think I would do it. But I did. I knew I was fixing to have major surgery . . . they had scheduled a thymectomy for the next Friday, and that’s like open-heart surgery. So I said I’m going to do it. And I did. It was awesome.
At first, I was on high doses of Mestinon, but after the thymectomy they tapered it down. Now I’m on normal doses. And I can pretty much do what I want as long as I take my medicine and get plenty of sleep. And I have to take something to sleep, which I don’t like. Before all this, give me four hours of sleep and I was ready to go. I went to law school when I was married with two kids . . . now, unfortunately, I’m in bed early. But I’m not complaining; I still get plenty of work done.
I have my ups and downs. When you have myasthenia, your muscles and ligaments are more susceptible to injury, and I’ve had a couple of knee injuries. I now have an electric muscle stimulator; it’s a pad that you put on your legs or arms. You program it, and when it’s on you tighten muscles, and when it’s off you relax. It’s a minute on and a minute off. And that helps to build muscle tone. I try to walk a little, even if it’s only 10 minutes a day, three times a day. Recently I started to have hot flashes . . . that’s not external heat, but it’s heat and it affects you as much as external heat does. So my doctor put me on estrogen, Cenestin, and it keeps them pretty much under control. With the myasthenia, the more Mestinon you take, the more you sweat, especially at night. I woke up some nights just drenched in
sweat.
My doctor thought it was a combination of the Mestinon and the hot flashes. But if I have night sweats now, I think it’s mostly from the Mestinon, and I hardly ever have them. That’s one of the best things about my doctor; I could tell her anything. And she took my concerns seriously.
A myasthenia crisis occurs when muscle weakness in the throat, chest, or diaphragm becomes so extreme that a person can’t breathe. In some cases, it can be triggered by a respiratory infection, fever, stress, surgery, lack of MG medication, or an adverse reaction to other drugs, such as cholesterol-lowering statins. MG crisis is a medical emergency that can require artificial respiration.
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