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Myasthenia gravis
Myasthenia gravis is a disorder of neuromuscular transmission leading to
fluctuating weakness and fatigue. It is one of the best known autoimmune
disorders and the antigens and disease mechanisms have well been
identified. Weakness is caused by circulating antibodies that block
acetylcholine receptors at the neuromuscular junction. A myasthenic
crisis may give rise to a generalized paralysis and assisted ventilation
may be required to sustain life.
Acetylcholine is a chemical substance that sustains muscle contraction
by stimulating the muscle fibers by binding to its receptors. The
immunologic reaction against these receptors and consecutive damage of
the neuromuscular endplate give rise to deficient stimulation of muscle
fibers. Patients frequently present with restricted movements of eye
muscles and eyelids, difficulty swallowing and speaking, generalized
weakness and fatigue. Myasthenia gravis is usually treated with
cholinesterase inhibitors, immunosuppressive drugs, thymectomy and
plasma exchange.
Although the term gravis means grave, recent developments in disease
treatment have made the prognosis more favourable. However a
considerable portion of patients still find it necessary to seek
admission to the intensive care units for assisted ventilation.
Overview
Myasthenia gravis is a chronic autoimmune neuromuscular disease
characterized by varying degrees of weakness of the skeletal (voluntary)
muscles of the body. The name myasthenia gravis, which is Latin and
Greek in origin, literally means "grave muscle weakness." With current
therapies, however, most cases of myasthenia gravis are not as "grave"
as the name implies. In fact, for the majority of individuals with
myasthenia gravis, life expectancy is not lessened by the disorder.
The hallmark of myasthenia gravis is muscle weakness that increases
during periods of activity and improves after periods of rest. Certain
muscles such as those that control eye and eyelid movement, facial
expression, chewing, talking, and swallowing are often, but not always,
involved in the disorder. The muscles that control breathing and neck
and limb movements may also be affected.
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Causes
Myasthenia gravis is caused by a defect in the transmission of nerve
impulses to muscles. It occurs when normal communication between the
nerve and muscle is interrupted at the neuromuscular junction - the
place where nerve cells connect with the muscles they control. Normally
when impulses travel down the nerve, the nerve endings release a
neurotransmitter substance called acetylcholine. Acetylcholine travels
through the neuromuscular junction and binds to acetylcholine receptors
which are activated and generate a muscle contraction.
In myasthenia gravis, antibodies block, alter, or destroy the receptors
for acetylcholine at the neuromuscular junction which prevents the
muscle contraction from occurring. These antibodies are produced by the
body's own immune system. Thus, myasthenia gravis is an autoimmune
disease because the immune system - which normally protects the body
from foreign organisms - mistakenly attacks itself.
Role of the thymus gland
The thymus gland, which lies in the upper chest area beneath the
breastbone, plays an important role in the development of the immune
system in early life. Its cells form a part of the body's normal immune
system. The gland is somewhat large in infants, grows gradually until
puberty, and then gets smaller and is replaced by fat with age. In
adults with myasthenia gravis, the thymus gland is abnormal. It contains
certain clusters of immune cells indicative of lymphoid hyperplasia - a
condition usually found only in the spleen and lymph nodes during an
active immune response. Some individuals with myasthenia gravis develop
thymomas (tumors on the thymus gland). Generally thymomas are benign,
but they can become malignant.
The relationship between the thymus gland and myasthenia gravis is not
yet fully understood. Scientists believe the thymus gland may give
incorrect instructions about the production of the acetylcholine
receptor antibodies, thereby setting the stage for the attack on
neuromuscular transmission.
Risk factors
Myasthenia gravis occurs in all ethnic groups and both genders. It most
commonly affects young adult women (under 40) and older men (over 60),
but it can occur at any age.
In neonatal myasthenia, the fetus may acquire immune proteins
(antibodies) from a mother affected with myasthenia gravis. Generally,
cases of neonatal myasthenia gravis are transient (temporary) and the
child's symptoms usually disappear within few weeks after birth. Other
children develop myasthenia gravis indistinguishable from adults.
Myasthenia gravis in juveniles is common.
Myasthenia gravis is not directly inherited nor is it contagious.
Occasionally, the disease may occur in more than one member of the same
family.
Rarely, children may show signs of congenital myasthenia or congenital
myasthenic syndrome. These are not autoimmune disorders, but are caused
by defective genes that control proteins in the acetylcholine receptor
or in acetylcholinesterase.
Symptoms
Although myasthenia gravis may affect any voluntary muscle, muscles that
control eye and eyelid movement, facial expression, and swallowing are
most frequently affected. The onset of the disorder may be sudden.
Symptoms often are not immediately recognized as myasthenia gravis.
In most cases, the first noticeable symptom is weakness of the eye
muscles. In others, difficulty in swallowing and slurred speech may be
the first signs. The degree of muscle weakness involved in myasthenia
gravis varies greatly among patients, ranging from a localized form,
limited to eye muscles (ocular myasthenia), to a severe or generalized
form in which many muscles - sometimes including those that control
breathing - are affected. Symptoms, which vary in type and severity, may
include a drooping of one or both eyelids (ptosis), blurred or double
vision (diplopia) due to weakness of the muscles that control eye
movements, unstable or waddling gait, weakness in arms, hands, fingers,
legs, and neck, a change in facial expression, difficulty in swallowing
and shortness of breath, and impaired speech (dysarthria).
Diagnosis
Unfortunately, a delay in diagnosis of one or two years is not unusual
in cases of myasthenia gravis. Because weakness is a common symptom of
many other disorders, the diagnosis is often missed in people who
experience mild weakness or in those individuals whose weakness is
restricted to only a few muscles.
The first steps of diagnosing myasthenia gravis include a review of the
individual's medical history, and physical and neurological
examinations. The signs a physician must look for are impairment of eye
movements or muscle weakness without any changes in the individual's
ability to feel things. If the doctor suspects myasthenia gravis,
several tests are available to confirm the diagnosis.
Blood testing
A special blood test can detect the presence of immune molecules or
acetylcholine receptor antibodies. Most patients with myasthenia gravis
have abnormally elevated levels of these antibodies. However, antibodies
may not be detected in patients with only ocular forms of the disease.
Edrophonium test
Another test is called the edrophonium test. This approach requires the
intravenous administration of edrophonium chloride or Tensilon®, a drug
that blocks the breakdown of acetylcholine and temporarily increases the
levels of acetylcholine at the neuromuscular junction. In people with
myasthenia gravis involving the eye muscles, edrophonium chloride will
briefly relieve weakness. Other methods to confirm the diagnosis include
a version of nerve conduction study which tests for specific muscle
fatigue by repetitive nerve stimulation. This test records weakening
muscle responses when the nerves are repetitively stimulated, and helps
to differentiate nerve disorders from muscle disorders. Repetitive
stimulation of a nerve during a nerve conduction study may demonstrate
decrements of the muscle action potential due to impaired
nerve-to-muscle transmission.
Single fiber electromyography
A different test called single fiber electromyography (EMG), in which
single muscle fibers are stimulated by electrical impulses, can also
detect impaired nerve-to-muscle transmission. EMG measures the
electrical potential of muscle cells. Muscle fibers in myasthenia
gravis, as well as other neuromuscular disorders, do not respond as well
to repeated electrical stimulation compared to muscles from normal
individuals.
CT & MRI
Computed tomography (CT) or magnetic resonance imaging (MRI) may be used
to identify an abnormal thymus gland or the presence of a thymoma.
Pulmonary function test
A special examination called pulmonary function testing — which measures
breathing strength — helps to predict whether respiration may fail and
lead to a myasthenic crisis.
Treatment
Today, myasthenia gravis can be controlled. There are several therapies
available to help reduce and improve muscle weakness. Medications used
to treat the disorder include anticholinesterase agents such as
neostigmine and pyridostigmine, which help improve neuromuscular
transmission and increase muscle strength. Immunosuppressive drugs such
as prednisone, cyclosporine, and azathioprine may also be used. These
medications improve muscle strength by suppressing the production of
abnormal antibodies. They must be used with careful medical followup
because they may cause major side effects.
Thymectomy, the surgical removal of the thymus gland (which is abnormal
in myasthenia gravis patients), improves symptoms in more than 50
percent of patients without thymoma and may cure some individuals,
possibly by re-balancing the immune system. Other therapies used to
treat myasthenia gravis include plasmapheresis, a procedure in which
abnormal antibodies are removed from the blood, and high-dose
intravenous immune globulin, which temporarily modifies the immune
system and provides the body with normal antibodies from donated blood.
These therapies may be used to help individuals during especially
difficult periods of weakness. A neurologist, along with the primary
care physician, will determine which treatment option is best for each
individual depending on the severity of the weakness, which muscles are
affected, and the individual's age and other associated medical
problems.
Myasthenic crises
A myasthenic crisis occurs when weakness affects the muscles that
control breathing, creating a medical emergency and requiring a
respirator for assisted ventilation. In patients whose respiratory
muscles are weak, crises - which generally call for immediate medical
attention - may be triggered by infection, fever, an adverse reaction to
medication, or emotional stress.
Prognosis
With treatment, the outlook for most patients with myasthenia gravis is
bright: they will have significant improvement of their muscle weakness
and they can expect to lead normal or nearly normal lives. Some cases of
myasthenia gravis may go into remission temporarily and muscle weakness
may disappear completely so that medications can be discontinued.
Stable, long-lasting complete remissions are the goal of thymectomy. In
a few cases, the severe weakness of myasthenia gravis may cause a crisis
(respiratory failure), which requires immediate emergency medical care.
(see above)
Research
Within the Federal Government, the National Institute of Neurological
Disorders and Stroke (NINDS), one of the Federal Government's National
Institutes of Health (NIH), has primary responsibility for conducting
and supporting research on myasthenia gravis.
Much has been learned about myasthenia gravis in recent years.
Technological advances have led to more timely and accurate diagnosis,
and new and enhanced therapies have improved management of the disorder.
Much knowledge has been gained about the structure and function of the
neuromuscular junction, the fundamental aspects of the thymus gland and
of autoimmunity, and the disorder itself. Despite these advances,
however, there is still much to learn. The ultimate goal of myasthenia
gravis research is to increase scientific understanding of the disorder.
Researchers are seeking to learn what causes the autoimmune response in
myasthenia gravis, and to better define the relationship between the
thymus gland and myasthenia gravis.
Today's myasthenia gravis research includes a broad spectrum of studies
conducted and supported by NINDS. NINDS scientists are evaluating new
and improving current treatments for the disorder. One such study is
testing the efficacy of intravenous immune globlin in patients with
myasthenia gravis. The goal of the study is to determine whether this
treatment safely improves muscle strength. Another study seeks to
understand the molecular basis of synaptic transmission in the nervous
system. The objective of this study is to expand current knowledge of
the function of receptors and to apply this knowledge to the treatment
of myasthenia gravis.
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