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James F. Howard, Jr., M.D.
Department of Neurology
The
University of North Carolina at Chapel Hill
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction. Much has been learned about the pathophysiology and immunopathology of myasthenia gravis during the past 20 years. What was once a relatively obscure condition of interest primarily to neurologists is now the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implications for the treatment of other autoimmune disorders.
EPIDEMIOLOGY
The prevalence of myasthenia
gravis in the United States is estimated at 14/100,000 population, approximately
36,000 cases in the United States. However, myasthenia gravis is probably under
diagnosed and the prevalence is probably 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 at onset has increased correspondingly, and
now males are more often affected than females, and the onset of symptoms is
usually after age 50.
CLINICAL PRESENTATION
Patients with myasthenia
gravis come to the physician complaining of specific muscle weakness and not of
generalized fatigue. Ocular motor disturbances, ptosis or diplopia, are the
initial symptom of myasthenia gravis in two-thirds of patients; almost all had
both symptoms within 2 years. Oropharyngeal muscle weakness, difficulty chewing,
swallowing, or talking, is the initial symptom in one-sixth of patients, and
limb weakness in only 10%. Initial weakness is rarely limited to single muscle
groups such as neck or finger extensors or hip flexors. The severity of weakness
fluctuates during the day, usually being least severe in the morning and worse
as the day progresses, especially after prolonged use of affected muscles.
The course of disease is variable but usually progressive. Weakness is restricted to the ocular muscles in about 10% of cases. The rest have progressive weakness during the first 2 years that involves oropharyngeal and limb muscles. Maximum weakness occurs during the first year in two-thirds of patients. In the era before corticosteroids were used for treatment, approximately one-third of patients improved spontaneously, one-third became worse, and one-third died of the disease. Spontaneous improvement frequently occurred early in the course. Symptoms fluctuated over a relatively short period of time and then became progressively severe for several years (active stage). The active stage is followed by an inactive state in which fluctuations in strength still occurred but are attributable to fatigue, intercurrent illness, or other identifiable factors. After 15 to 20 years, weakness often becomes fixed and the most severely involved muscles are frequently atrophic (burnt-out stage). Factors that worsen myasthenic symptoms are emotional upset, systemic illness (especially viral respiratory infections), hypothyroidism or hyperthyroidism, pregnancy, the menstrual cycle, drugs affecting neuromuscular transmission, and increases in body temperature.
PATHOPHYSIOLOGY OF MYASTHENIA GRAVIS
The
normal neuromuscular junction releases acetylcholine (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.
In acquired myasthenia gravis, the post-synaptic muscle membrane is distorted
and simplified, having lost its normal folded shape. The concentration of ACh
receptors on the muscle end-plate membrane is reduced, and antibodies are
attached to the membrane. 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.
THE THYMUS IN MYASTHENIA GRAVIS
Thymic
abnormalities are clearly associated with myasthenia gravis but the nature of
the association is uncertain. Ten percent of patients with myasthenia gravis
have a thymic tumor and 70% have hyperplastic 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 causes
an immune-mediated attack on AChR in myasthenia gravis. The thymus contains all
the necessary elements for the pathogenesis of myasthenia gravis: myoid cells
that express the AChR antigen, antigen presenting cells, and immunocompetent
T-cells. Thymus tissue from patients with myasthenia gravis produces AChR
antibodies when implanted into immunodeficient mice. However, it is still
uncertain whether the role of the thymus in the pathogenesis of myasthenia
gravis is primary or secondary.
Most thymic tumors in patients with myasthenia gravis are benign, well-differentiated and encapsulated, and can be removed completely at surgery. It is unlikely that thymomas result from chronic thymic hyperactivity because myasthenia gravis can develop years after thymoma removal and the HLA haplotypes that predominate in patients with thymic hyperplasia are different from those with thymomas. Patients with thymoma usually have more severe disease, higher levels of AChR antibodies, and more severe EMG abnormalities than patients without thymoma. Almost 20% of patients with myasthenia gravis whose symptoms began between the ages of 30 and 60 years have thymoma; the frequency is much lower when symptom onset is after age 60.
DIAGNOSTIC PROCEDURES
The Edrophonium
Chloride (Tensilon) Test
Weakness caused by abnormal neuromuscular
transmission characteristically improves after intravenous administration of
edrophonium chloride. Some patients who don't respond to intravenous edrophonium
chloride may respond to intramuscular neostigmine, because of the longer
duration of action. Intramuscular neostigmine is particularly useful in infants
and children whose response to intravenous edrophonium chloride may be too brief
for adequate observation. In some patients, a therapeutic trial of daily oral
pyridostigmine may produce improvement that can't be appreciated after a single
dose of edrophonium chloride or neostigmine.
Antibodies Against Acetylcholine Receptor (AchR)
Seventy
four percent of patients with acquired generalized myasthenia and 54% with
ocular myasthenia have serum antibodies that bind human AChR. The serum
concentration of AChR antibody varies widely among patients with similar degrees
of weakness and cannot predict the severity of disease in individual patients.
Approximately 10% of patients who do not have binding antibodies, have other
antibodies that modulate the turnover of AChR in tissue culture. The
concentration of binding antibodies may be low at symptom onset and become
elevated later. AChR binding antibodies concentrations are sometimes increased
in patients with systemic lupus erythematosus, inflammatory neuropathy,
amyotrophic lateral sclerosis, rheumatoid arthritis taking D-penicillamine,
thymoma without myasthenia gravis, and in normal relatives of patients with
myasthenia gravis. False positive tests are reported when blood is drawn within
48 hours of a surgical procedure involving the use of general anesthesia and
muscle relaxants. In general, an elevated concentration of AChR binding
antibodies in a patient with compatible clinical features confirms the diagnosis
of myasthenia gravis, but normal antibody concentrations do not exclude the
diagnosis.
Electromyography
Repetitive Nerve Stimulation (RNS)
The
amplitude of the compound muscle action potential (CMAP) elicited by repetitive
nerve stimulation is normal or only slightly reduced in patients without MG. The
amplitude of the fourth or fifth response to a train of low frequency nerve
stimuli falls at least 10% from the initial value in myasthenic patients. This
decrementing response to RNS is seen more often in proximal muscles, such as the
facial muscles, biceps, deltoid, and trapezius than in hand muscles. A
significant decrement to RNS in either a hand or shoulder muscle is found in
about 60% of patients with myasthenia gravis.
Single Fiber EMG (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 muscle weakness may have increased jitter only in
facial muscles. Increased jitter is a nonspecific sign of abnormal neuromuscular
transmission and can be seen in other motor unit diseases. Normal jitter in a
weak muscle excludes abnormal neuromuscular transmission as the cause of
weakness.
Comparison of Diagnostic Techniques
Intravenous edrophonium
chloride is often diagnostic in patients with ptosis or ophthalmoparesis, but is
less useful when other muscles are weak. Elevated serum concentrations of AChR
binding antibodies virtually assures the diagnosis of myasthenia gravis, but
normal concentrations do not exclude the diagnosis. Repetitive nerve stimulation
confirms impaired neuromuscular transmission but is not specific to myasthenia
gravis and is frequently normal in patients with mild or purely ocular disease.
The measurement of jitter by SFEMG is the most sensitive clinical test of
neuromuscular transmission and is abnormal in almost all patients with
myasthenia gravis. A normal test in a weak muscle excludes the diagnosis of
myasthenia gravis, but an abnormal test can occur when other motor unit
disorders cause defects in neuromuscular transmission.
TREATMENT
A controlled clinical trial has
never been reported for any medical or surgical modality used to treat
myasthenia gravis. All recommended regimens are empirical and experts disagree
on treatments of choice. Treatment decisions should be 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
ChE inhibitors retard the
enzymatic hydrolysis of ACh at cholinergic synapses, so that ACh accumulates at
the neuromuscular junction and its effect is prolonged. ChE inhibitors cause
considerable improvement in some patients and little to none in others. Strength
rarely returns to normal. Pyridostigmine bromide (Mestinon) and neostigmine
bromide (Prostigmin) are the most commonly used ChE inhibitors. No fixed dosage
schedule suits all patients. The need for ACh 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 get stronger, others do not change, and still others become
weaker. Adverse effects of ChE inhibitors may result from ACh accumulation at
muscarinic receptors on smooth muscle and autonomic glands and at nicotinic
receptors of skeletal muscle. Central nervous system side effects are rarely
seen with the doses used to treat myasthenia gravis. Gastrointestinal complaints
are common; queasiness, loose stools, nausea, vomiting, abdominal cramps, and
diarrhea. Increased bronchial and oral secretions are a serious problem in
patients with swallowing or respiratory insufficiency. Symptoms of muscarinic
overdosage may indicate that nicotinic overdosage (weakness) is also occurring.
Excessive nicotinic receptor overdosage results in Myasthenic Crisis
characterized by severe generalized weakness and respiratory failure.
Thymectomy
Thymectomy is recommended for most patients with
myasthenia gravis. Most reports do not correlate the severity of weakness before
surgery and the timing or degree of improvement after thymectomy. The maximal
favorable response generally occurs 2 to 5 years after surgery. However, the
response is relatively unpredictable and significant impairment may continue for
months or years after surgery. Sometimes, improvement is only appreciated in
retrospect. The best responses to thymectomy are in young people early in the
course of their disease, but improvement can occur even after 30 years of
symptoms. Patients with disease onset after the age of 60 rarely show
substantial improvement from thymectomy. Patients with thymomas do not respond
as well to thymectomy as do patients without thymoma.
Corticosteroids
Marked improvement or complete relief of
symptoms occurs in more than 75% of patients treated with prednisone, and some
improvement occurs in most of the rest. Much of the improvement occurs in the
first 6 to 8 weeks, 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. The most
predictable response to prednisone occurs when treatment begins with a daily
dose of 1.5 to 2 mg/kg/day. About one-third of patients become weaker
temporarily after starting prednisone, usually within the first 7 to 10 days,
and lasting for up to 6 days. Treatment can be started at low dose to minimize
exacerbations; the dose is then slowly increased until improvement occurs.
Exacerbations may also occur with this approach and the response is less
predictable. The major disadvantages of chronic corticosteroid therapy are the
side effects.
Immunosuppressant Drugs
Azathioprine reverses symptoms in
most patients but the effect is delayed by 4 to 8 months. Once improvement
begins, it is maintained for as long as the drug is given, but symptoms recur 2
to 3 months after the drug is discontinued or the dose is reduced below
therapeutic levels. Patients who fail corticosteroids may respond to
azathioprine and the reverse is also true. Some respond better to treatment with
both drugs than to either 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 inhibits predominantly T-lymphocyte-dependent immune responses and is sometimes beneficial in treating myasthenia gravis. Most patients with myasthenia gravis improve 1 to 2 months after starting cyclosporine and improvement is maintained as long as therapeutic doses are given. Maximum improvement is achieved 6 months or longer after starting treatment. After achieving the maximal response, the dose is gradually reduced to the minimum that maintains improvement. Renal toxicity and hypertension, the important adverse reactions of cyclosporine. Many drugs interfere with cyclosporine metabolism and should be avoided or used with caution .
Cyclophosphamide has been used intravenously and orally for the treatment of myasthenia gravis. More than half of patients become asymptomatic after one year. Side effects are common. Life-threatening infections are an important risk in immunosuppressed patients, but in our experience, this risk is limited to patients with invasive thymoma. The long-term risk of malignancy is not established, but there are no reports of an increased incidence of malignancy in patients with myasthenia gravis receiving immunosuppression.
Plasma Exchange
Plasma exchange is used as a short-term
intervention for patients with sudden worsening of myasthenic symptoms for any
reason, 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
myasthenia gravis 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)
Several groups have
reported a favorable response to high-dose (2 grams/kg infused over 2 to 5 days)
IVIG. Possible mechanisms of action include down-regulation of antibodies
directed against AChR and the introduction of anti-idiotypic antibodies.
Improvement occurs in 50 to 100% of patients, usually beginning within 1 week
and lasting for several weeks or months. The common adverse effects of IVIG are
related to the rate of infusion. The mechanism of action is not known but is
probably non-specific down regulation of antibody production.
THE FUTURE
The future of Myasthenia Gravis
lies in the elucidation of the molecular immunology of the anti-acetylcholine
receptor response with the goal of developing a rational treatment for the
illness that will cure the abnormality in the immune system that results in the
AChR immune response. To this end, six broad categories of theoretical treatment
strategies need to be explored. First, those treatments which target the
antigen specific B-cells; Second, those treatments which target the
antigen specific CD4+ T-cells; Third, those treatments which interfere
with co-stimulatory response for antigen presentation, Fourth, treatments
aimed at inducing tolerance or anergy of the CD4+ T-cell to the autoantigen or
the CD4+ epitopes; Fifth, those treatments designed to stimulate those
immunological circuits which activate CD8+ cells specific for the activation
antigens expressed by CD4+ cells and Sixth, those treatments which
intervene with cytokine function and discourage autoimmune mediated inflammatory
responses.