Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (40 page)
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Weak in the Knees—Myasthenia Gravis
There were signs that there was something wrong for a while. My husband and some of my friends had thought I was taking prescription tranquilizers, because my voice would start slurring. And my secretary said it had gotten to the point that I would dictate a letter to Mr. Smith and say Mr. Jones. I would forget phone numbers. I was clumsy; I would step wrong and fall . . . I couldn’t put the backs on earrings. Or use a little calculator. Little things like that. But because I’m such a Type-A person, I masked the symptoms. Then I collapsed in church on July 4, 1999 . . . after the service, I walked over to hug a friend, and suddenly I didn’t know where I was. And my legs were like real rubbery. My husband got me out of there, got me in the car, and drove to the emergency room. The neurologist thought maybe it was a TIA or an aneurysm and was going to send me to a larger hospital, but the doctor on call said it was stress: “Stress does funny things to you,” he said. They did a bunch of tests but couldn’t find anything, so they sent me home. The following morning, after my husband left for work, I went to brush my teeth and choked. And I panicked. I crawled upstairs to the phone and paged him, and then we went back to the hospital. They did the blood test and they did the Tensilon test. It was unreal. When they gave me the Tensilon, all of my symptoms disappeared. And we cried because we knew what was facing me. I started on medication that day.
J
ACKIE
, 64
M
yasthenia gravis (MG) involves miscommunication between nerves and muscles. It results from an autoantibody attack on the receptors for a chemical that carries signals between the nervous system and voluntary muscles—the muscles we have direct control over.
Up to 60,000 people in the United States may be affected by MG, three to four times more women than men up until the age of 40. In older age, more men than women are affected. Symptoms usually appear after age 50.
1
Once considered a fatal disease, MG can now be controlled successfully, and a majority of people with MG live productive lives.
When we pick up a pencil or take a walk, we may not be conscious of directing specific muscles, but our brain has to tell those muscles to move. That message is sent by a chemical called
acetylcholine (ACh)
, released at the
neuromuscular junction
, the spot where the motor nerve terminal meets a folded muscle membrane called the
end plate
. When the brain stimulates the motor nerve, acetylcholine is sent out in little packets (
vesicles
) that cross the space between the muscle and nerve (the
synapse
) and binds to receptors concentrated on the peaks of each end-plate fold. When the vesicles bind to
acetylcholine receptors (AChR)
, it stimulates the muscle to contract. We couldn’t pick up that pencil without ACh.
The Neuromuscular Junction
In autoimmune myasthenia gravis, antibodies to proteins on
ACh receptors (anti-AChR antibodies)
cause the loss of those receptors, so that fewer remain.
2
The muscle end plate also loses its folded shape, further reducing the number of ACh receptors and widening the space between muscle and nerve. Anti-AChR antibodies also trigger the deposit of proteins called
complement
at the neuromuscular junction, further increasing receptor loss.
3
,
4
The upshot: while there’s plenty of ACh, there are fewer receptors to pick it up, and the membrane becomes less sensitive.
The effects of ACh are reduced, so there’s less chance that a nerve impulse will provoke a muscle contraction, leading to muscle weakness, explains Arnold I. Levinson, MD, emeritus professor of medicine and neurology associate dean for research, Perelman School of Medicine, who has been researching the origins of MG.
“The hallmark of the disease is a marked reduction in the number of receptors but a normal amount of acetylcholine. There is also actual destruction of the muscle end plate by the autoantibodies and complement,” says Dr. Levinson. The fewer the ACh receptors the worse the symptoms of MG.
Abnormal cell growth in the thymus may lead to production of autoantibodies. Ten percent of people with MG have small, benign tumors in the thymus (called
thymomas
); 60 to 70 percent have abnormal development of B-cell-enriched areas (
germinal center hyperplasia
) in the thymus, says Dr. Levinson. Thymic abnormalities may result in sensitization of B cells to produce anti-AChR autoantibodies.
5
Defective Treg cells also play a role.
6
“Years ago, before we even knew about immune cells, it was clear the thymus was involved in myasthenia, so the thymus was routinely removed in patients with myasthenia. And patients got better. We still don’t know why they get better, but to this day thymectomy is still a first-line therapy for patients before the age of 60,” remarks Dr. Levinson. “Levels of autoantibodies drop after thymectomy, but the improvement is not necessarily due to lower antibody titers. The amount of circulating autoantibodies does not correlate to the severity of myasthenia.” More data should be forthcoming from an international trial of thymectomy.
“We think the thymus plays a primary role in myasthenia, and we think that self-tolerance is actually broken in the thymus. There are AChR-reactive cells that are not eliminated in the thymus and are exported into the circulation. We’re testing the hypothesis in animals that some inflammatory event allows these T cells, which react with acetylcholine receptors, to travel back to the thymus, where they’re activated by locally expressed AChR in people with myasthenia,” says Dr. Levinson.
Some research suggests that molecular mimicry may play a role in autoimmune myasthenia gravis, with immune cells mistaking ACh receptors for a virus (possibly a
herpes simplex
virus) or bacteria.
7
MG may also have a genetic component, since a variety of autoimmune diseases are associated with myasthenia (in both patients and their family members—see “MG Clusters,”
page 330
). It’s possible that an inherited defect in immune regulation may predispose people to myasthenia gravis.
Genetic defects also cause
congenital myasthenia syndrome (CMS)
—a group of disorders where abnormalities of the neuromuscular junction cause muscle weakness. However, CMS is not considered autoimmune, and the autoantibodies that attack the neuromuscular junction in MG are not found. CMS is relatively rare and appears in childhood.
Jackie’s story continues:
I was lucky I was diagnosed quickly. And I think it was because I had a female doctor . . . I knew, and my husband Joe knew, that I wasn’t crazy. But you feel that way when doctors dismiss you and say, “Oh, it’s just stress.” Even one of my best friends said to me, “Maybe you just need to chill out and take some time off.” And really, the symptoms were deceptive. Now we look back and we know what was going on. But I was extremely fortunate.
I’ve heard horror stories from other women with this disease going two and three years and even more before they’re diagnosed. Going from doctor to doctor, and all of them saying it’s all in their heads. After I was diagnosed with MG, the doctor who told me it was stress came into my room and I told him, “I’m going to make you a better doctor. You blew off my symp
toms as stress, and embarrassed me in front of my family and friends. You have to start to think about your attitude.” He needed to know that. And he did change the way he treats his patients. But he wasn’t unusual. Many doctors tell a woman who has complaints he can’t pin down, “Oh, it’s in your head,” when he would start doing every kind of test if it was a man. And it shouldn’t be that way.
The first symptom of MG is usually droopy eyelids (
ptosis
). Muscle weakness around the eyes (
ocular muscles
) and/or the development of double vision (
diplopia
) are usually what bring women to see their doctor. According to the Myasthenia Gravis Foundation of America (MGFA), two-thirds of patients experience one or both symptoms at first.
1
Eyes may not close completely, and eye movements may be difficult or tiring. For example, looking upward and trying to hold the eyes open may result in eyelid drooping that gets progressively worse.
There can be problems with the bulbar muscles around the mouth and throat, causing problems speaking, chewing, swallowing, and even smiling. Such problems are the initial symptoms in around one-sixth of patients.
1
Women can also experience weakness in the arms or legs (this is less common as a first symptom of MG, occurring in only around 10 percent of cases).
1
Usually, muscle weakness is less severe in the morning and worsens as the day goes on, especially if the affected muscles are used for long periods of time.
While MG is a progressive disease, it doesn’t always cause rapid deterioration. In 10 to 15 percent of cases, weakness is restricted to the eye muscles. Many women will have some progressive weakness during the first year or two involving the mouth and throat (
oropharyngeal
) muscles and/or the limb muscles. But the disease can stabilize over time. “If myasthenia doesn’t become
severe early on, it may stay on a plateau. For example, if muscle weakness is restricted to the eyes for the first three years, it’s likely to remain there in 90 percent of cases. It’s unusual for the disease to be mild for 10 years and then start progressing,” remarks Janice M. Massey, MD, Professor of Neurology and Chief of the Division of Neuromuscular Diseases at Duke University Medical Center.
Often a woman may have mild weakness and not attach much importance to it, and up to 25 percent of people may see some remission of initial symptoms. So it can be a while before she sees a doctor, especially if she doesn’t have classical symptoms such as drooping eyes or double vision. Mild symptoms also may not be constant; ptosis may get worse toward the end of the day, or with exercise, and improve after rest. “In fact, it’s not unusual for patients not to realize the degree of weakness they have had until it’s improved by treatment,” adds Dr. Massey.
Conversely, if MG worsens rapidly over days to weeks, especially in the muscles involving speaking, chewing, or swallowing, that can indicate a case that needs swift and aggressive treatment, says Dr. Massey. “In rare cases we see a patient whose symptoms have been stable for over 10 years get the flu or another illness, something that activates the immune system, and their disease can progress to a more serious level.”
In mild cases, a diagnosis may be delayed until symptoms start to worsen, sometimes by coexisting thyroid disease. An overactive thyroid (
hyperthyroidism
) or an underactive thyroid (
hypothyroidism
) can cause muscle weakness, and
Graves’ disease
may mimic the eye muscle weakness of MG. In women with myasthenia, mild symptoms that had not caused concern previously may worsen with the onset of thyroid disease to the point where a woman may finally seek medical attention. “Changes in thyroid function, either hypo- or hyperthyroidism, can produce true worsening of disease activity,” comments Dr. Massey.
Myasthenic symptoms can be worsened by medications. The most common drugs that affect myasthenia are antibiotics, particularly mycin drugs (like
strep
tomycin
),
fluoroquinolone
(like
ciprofloxacin
),
macrolide
antibiotics (like
azithromycin
),
botulinum toxins
,
beta-blockers
, and other cardiac drugs, which have a direct effect on neuromuscular transmission. Even nonprescription drugs can exacerbate symptoms of MG—for example, milk of magnesia,
because magnesium affects the neuromuscular junction. A partial list of medications that exacerbate myasthenia appears on
page 337
.
Myasthenic symptoms can also be worsened temporarily by illness (particularly respiratory viral infections), increases in body temperature in hot weather (especially in high humidity), stress, emotional upsets, and pregnancy. “Women can become profoundly weak after walking in the heat or working in the garden. After they cool off and rest, within a day or so they completely recuperate. That exacerbation doesn’t indicate a worsening of disease,” Dr. Massey emphasizes.
“If a patient comes in whose symptoms have gotten worse out of the blue, I will ask her if she’s had a recent viral infection, if she has been put on any new medications, or if she is pregnant. I will also check her thyroid function. Sorting out the causes of symptoms and what may be causing them can be complicated, since there are many factors that could contribute.”
Fifteen percent of myasthenia patients will present with thymoma, although this is more common in men. In this case, removal of the tumor and the residual thymus tissue (
thymoma/thymectomy
) can cure the disease.
