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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.
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