Clinical manifestations and diagnosis of myasthenia gravis
INTRODUCTION — The diagnosis of myasthenia gravis (MG) can be established by
clinical and serologic testing . It is useful, however, to first review the clinical
manifestations of this disorder to appreciate the settings in which it should be
suspected. The pathogenesis and treatment of this disorder are discussed separately.
(See "Pathogenesis of myasthenia gravis" and see "Treatment of myasthenia
Myasthenia in a neonate may result from transplacental passage of maternal
antibodies that interfere with function of the neuromuscular junction, or it may be
the result of a mutation that affect junctional function. Neonatal and congenital
myasthenia are discussed separately. (See "Neuromuscular junction disorders in
CLINICAL MANIFESTATIONS — Myasthenia presents in two main groups of
patients: women in their 20s and 30s and men over the age of 60. The cardinal
feature of the illness is its association with fatigue as the degree of muscle weakness
increases with exercise of the affected muscles and improves with rest .
Weakness often begins in the eyes, but may begin in the bulbar muscles or the
muscles of the limbs and trunk.
Eye muscles — Weakness of the eye muscles can lead to ptosis, the degree of
which can be variable, switching from one eye to the other on separate examinations
and occasionally increasing with sudden exposure to bright light. The extraocular eye
muscles are also often involved. The clinical manifestations of these changes vary
from subtle blurring of vision to severe diplopia. (See "Neuromuscular diplopia").
Physical examination may reveal unusual eye movements that do not conform to the
anatomy of one nerve or muscle. The pupils are always spared in myasthenia gravis,
helping in the differentiation from other disorders such as botulism.
Bulbar muscles — A "myasthenic snarl" may be seen when the bulbar muscles are
affected. This problem of facial muscle weakness occurs when smiling and can cause
embarrassment. Other bulbar manifestations include nasal speech devoid of
consonant sounds due to weakness of the palate and tongue, difficulty chewing, and
less often difficulty swallowing and choking on liquids. The problem with chewing
may be so severe that the patient must support his or her chin with a hand to finish
chewing something tough. Supporting the chin may also be necessary if there is neck
extensor weakness which can cause the head to fall forward out of the patient's
Limb and trunk muscles — Involvement of the limbs and trunk in myasthenia
produces symptoms similar to other muscle diseases. The proximal limbs are most
commonly affected. However, predominately distal presentations of otherwise typical
myasthenia occurred in 6 of 84 patients in one prospective series .
One important feature suggesting myasthenia is the marked association with
fatiguability. The respiratory muscles can be affected in advanced disease, producing
a potentially life-threatening situation called "myasthenic crisis". (See "Treatment of
DIAGNOSIS OF MYASTHENIA — The diagnostic approach to myasthenia begins
with the physical examination and then proceeds to more specific testing. The major
aim on physical examination is to test for fatiguability of the different muscle groups:
Ptosis induced by fatigue can be demonstrated by having the patient sustain
upward gaze by looking at your finger. Slowly the lids begin to drift down. This sign,
if present, is very useful in the Tensilon test discussed below.
Fatigue of the upper extremities can be tested for by having the patient sit with
arms stretched in front, looking for a slow downward drift. Grip fatigue can be
measured with a dynamometer that the patient grasps repetitively.
Lower extremity fatigue can be demonstrated by having the patient step up and
down from a footstool as if climbing stairs. This gets progressively more difficult and
the patient begins to push off their knee with their arm in order to help the
Tensilon test — Once a group of muscles is shown to weaken with exercise and
improve with rest, the diagnosis of myasthenia gravis can be confirmed most easily
by an intravenous injection of the acetylcholinesterase inhibitor Tensilon
(edrophonium chloride; 10 mg/mL). Tensilon begins to act in 30 to 60 seconds and
its effect lasts five to 10 minutes. The ensuing potentiation of the muscarinic effects
of acetylcholine is not without risk, especially in the elderly; as a result, atropine (0.5
to 2.0 mg) should be available if a severe cholinergic reaction occurs. Signs of
cholinergic crisis include sweating, increased weakness and respiratory secretions,
laryngospasm, bradycardia, hypotension, nausea, and vomiting.
To minimize the risk of an adverse reaction, a test dose of 1 mg (0.1 mL) of Tensilon
should be given. After one minute, a further 4 mg (0.4 mL) is given and, if no
change in the examination is noted in one minute, the remainder of the vial (5 mg,
0.5 mL) is given and the response quantified. However, quantifying the response can
be a problem. Although sustained upward gaze that produces ptosis can quickly
reverse with Tensilon, this response is often absent and, even if present, can be
open to interpretation. A grip strength test with a dynamometer is more useful if the
grip muscles are affected, since this can be quantified and the response repeated.
The Tensilon test is associated with both false negative and false positive results. As
an example, it is negative in up to 50 percent of patients presenting with eye signs
alone and may be difficult to interpret in patients with involvement of other muscle
groups. On the other hand, a positive ocular test is not specific for myasthenia
gravis, also occurring in other conditions, such as amyotrophic lateral sclerosis (ALS)
and cavernous sinus lesions, which can present in a similar fashion (see below) .
As a result, it is often necessary to perform other confirmatory tests: immunologic
testing for acetylcholine receptor antibodies; and electromyography.
Acetylcholine receptor antibodies — Myasthenia gravis is a condition that fulfills
all the major criteria for a disorder mediated by autoantibodies against the
acetylcholine receptor (AChR-Ab) . (See "Pathogenesis of myasthenia gravis").
The antibody is present in at least 80 to 90 percent of affected patients.
The condition can be passively transferred to an animal model.
Injection of the human antigen in other species produces a model disease.
Reduction in antibody levels is associated with clinical improvement.
As a first step, therefore, the presence of circulating AChR-Ab should be evaluated in
the patient suspected of having myasthenia gravis. The demonstration of such
antibodies in a competent laboratory is usually diagnostic of myasthenia. These
antibodies are found in 93, 88, and 71 percent of individuals with moderate to severe
generalized myasthenia gravis, mild generalized myasthenia, and ocular myasthenia,
There are few reports of false-positive results and these occur in disorders that are
not usually confused with myasthenia (eg, primary biliary cirrhosis, tardive
dyskinesia, autoimmune thyroiditis, systemic lupus erythematosus, thymoma without
myasthenia, and amyotrophic lateral sclerosis) [6-12]. As with the Tensilon test,
however, some patients with ocular and even significant generalized myasthenia
have a false negative test for AChR-Ab; thus, a negative test does not exclude the
disease (see "Conditions that mimic ocular myasthenia" below).
Antibody-negative myasthenia — Antibody-negative or seronegative myasthenia
gravis (SNMG) refers to patients with clinical myasthenia who have a negative
standard assay for AChR-Ab, which occurs in approximately 10 to 20 percent of
affected patients [5,13].
In one review, the use of multiple AChR-Ab tests, such as binding, blocking, and
modulating antibodies, did not appreciably alter the number of individuals found to
be antibody negative . In other studies, AChR blocking and modulating
antibodies are positive in approximately 5 percent of patients with negative binding
These additional AChR antibody tests may fulfill an important role when screening for
a thymoma. The presence of a thymoma is suggested if AChR modulating antibodies
are present and produce more than 90 percent loss of AChR sites in cultured human
muscle cells .
Muscle-specific receptor tyrosine kinase antibodies — Some patients with
seronegative myasthenia gravis have autoantibodies directed against another target
on the surface of the muscle membrane, the muscle-specific receptor tyrosine kinase
(MuSK). MuSK antibody positive myasthenia gravis may have a different cause and
pathologic mechanism than AChR-Ab positive disease . (See "Pathogenesis of
myasthenia gravis", section on Muscle-specific receptor tyrosine kinase antibodies).
The diagnostic utility of MuSK testing in clinical practice is probably limited, as
myasthenia gravis is a relatively rare disorder, and antibody negative myasthenia
gravis is even less common. In addition, the pathophysiological link between MuSK
antibodies and myasthenia gravis remains unclear.
In the appropriate clinical setting (lack of AChR-Ab and typical clinical features listed
below), MuSK testing can clarify the diagnosis and perhaps direct treatment .
The notion that SNMG patients with MuSK antibodies do not have thymic pathology
[16,17] is one rationale for testing for MuSK in SNMG. (See "Pathogenesis of
myasthenia gravis", section on Muscle-specific receptor tyrosine kinase antibodies).
However, initial management of clinically apparent myasthenia should be the same
for patients with or without AChR antibodies; this would change only if future studies
find additional therapeutic differences related to MuSK status.
MuSK antibody testing is commercially available in the United States. In the UK
testing can be arranged through Dr. Angela Vincent's laboratory; more information is
available at the following internet address:
Clinical features — The following observations have been made regarding the
clinical features of "seronegative" myasthenia, including MuSK positive myasthenia
Onset at any age
Marked bulbar and neck or respiratory weakness
Bulbar and especially tongue atrophy
No thymic pathology and lack of responsiveness to thymectomy
Poor responsiveness to anticholinergic medications
Good responsiveness to plasma exchange and immunosuppression
Electromyography and repetitive nerve stimulation — Electromyography (EMG)
takes advantage of the main physiologic defect in myasthenia - the partial blockade
of neuromuscular transmission. Repetitive stimulation normally leads to a
decremental response in compound action potentials on EMG as acetylcholine release
drops with succeeding stimuli. This produces excitatory postsynaptic potentials which
fail to reach the threshold needed for generating a muscle action potential in
myasthenia because of the combination of less acetylcholine and decreased number
of available receptors.
The test is performed by placing the recording electrode over the belly of a muscle
and stimulating the motor nerve to that muscle. The height of the recorded
compound action potential is proportional to the number of muscle fibers firing when
a supramaximal stimulus is used. At a stimulation rate of 1 to 5/second (usually
3/second), the muscle will show a loss of amplitude of greater than 10 percent by
the fourth compound action potential (show figure).
One of the problems with EMG is optimal muscle selection. Proximal muscles are
more likely to be positive but are also harder to stimulate. Thus, sampling several
muscles is recommended to increase the sensitivity of the test. As with the AChR-Ab
test, repetitive stimulation is less likely to be positive in ocular myasthenia. Single
fiber EMG and the Lancaster red-green test of ocular motility, although not readily
available, may help confirm myasthenia in this setting .
CONDITIONS THAT ARE ASSOCIATED WITH MYASTHENIA — Autoimmune
disorders and thymic tumors can cause myasthenia and, like thyroid disease, they
can also exacerbate underlying myasthenia. Hyperthyroidism, for example, is
associated with myasthenia in three to eight percent of cases (see below) .
Thymic tumors and other malignancies — The thymus is intimately involved in
the pathogenesis of myasthenia gravis. (See "Pathogenesis of myasthenia gravis").
It is postulated that all patients with myasthenia have B cells that produce AChR-Ab
in the thymus. In addition, 75 percent of patients with myasthenia have thymic
disease; thymic hyperplasia is most common (85 percent) but various tumors may
also be seen .
The thymic tumors are usually noninvasive cortical thymomas, but invasive thymic
carcinoma can occur. (See "Pathology of mediastinal tumors" and see "Clinical
presentation and management of thymoma and thymic carcinoma"). Thus, CT scan
or MR imaging of the mediastinum is an important component of the evaluation of
myasthenia gravis. It has been suggested that the concurrent presence of antibodies
directed against titin (a striated muscle antigen) are predictive of a thymic epithelial
tumor (sensitivity 69 percent and specificity 100 percent in one series) [25,26].
Myasthenia gravis has also been associated with extrathymic tumors, such as small
cell lung cancer and Hodgkin's disease [27-29]. Cure of the underlying disease may
lead to resolution of myasthenic symptoms .
Autoimmune disorders — Systemic lupus erythematosus and rheumatoid arthritis
may be associated with myasthenia. In rare cases, myasthenia precedes the other
manifestations of these diseases. Thus, screening for antinuclear antibodies and
rheumatoid factor should also be part of the initial evaluation.
CONDITIONS THAT MIMIC OCULAR MYASTHENIA — Most of the conditions that
are likely to be confused with myasthenia gravis involve weakness of the extraocular
muscles. The diagnosis of ocular myasthenia is often difficult to confirm, since the
ancillary tests described above are often negative. It is estimated that the Tensilon
test is positive in 50 to 85 percent of such patients, AChR-Ab in 50 to 70 percent,
and repetitive stimulation in 30 to 40 percent . In this setting, the absence of
positive confirmatory tests for thyroid disease, a mitochondrial disorder, and
brainstem pathology may permit a tentative diagnosis of ocular myasthenia by
Thyroid disease — Grave's disease produces unusual eye movements due to a
constrictive hypertrophic ophthalmopathy. The correct diagnosis is often obvious
when exophthalmos is present. However, thyroid disease can coexist with
myasthenia gravis. As a result, screening thyroid studies are usually a good idea
before treatment is instituted, even when the diagnosis of myasthenia gravis is clear.
Kearns-Sayre syndrome — The Kearns-Sayre syndrome is a mitochondrial
disorder that produces progressive ophthalmoplegia and ptosis. As it progresses,
generalized muscle weakness can occur. Associated problems with cerebellar disease
and retinal degeneration eventually make this disorder distinct from myasthenia.
Muscle biopsy shows "ragged red" fibers and plasma lactate and pyruvate levels are
elevated. (See "Myopathies affecting the extraocular muscles in children", section on
Brainstem pathology — Structural disease of the brainstem can cause isolated
ocular disease. Parasellar tumors and aneurysms, for example, can impair function of
the third, fourth, and sixth cranial nerves, leading to symptoms similar to ocular
myasthenia. Searching for fifth nerve dysfunction in such patients (especially an
absent corneal reflex) may confirm a structural lesion. CT or MRI scanning to exclude
these disorders is advocated by some neurologists when evaluating patients with
ocular myasthenia .
CONDITIONS THAT MIMIC GENERALIZED MYASTHENIA — There are a number
of conditions that can mimic myasthenia clinically. However, careful history, physical
examination, and testing usually allow the correct diagnosis to be established.
Depression — Because of the distinctive problem of muscle fatigue in myasthenia,
the disease is often unrecognized or, worse, is mistaken for a conversion reaction.
This is especially true when the patient's demeanor suggests depression. It is
therefore important to differentiate generalized fatigue from muscle fatigue produced
by repetitive muscle contraction. As an example, the depressed patient complains of
fatigue that is often maximal in the morning; in comparison, patients with
myasthenia often relate their fatigue to a specific activity, such as climbing stairs,
brushing their hair, or a full day at work, many of which are maximal in the evening.
Amyotrophic lateral sclerosis — ALS is a relentlessly progressive disease that,
like myasthenia, can involve the bulbar muscles and can produce a false positive
Tensilon test and even a false positive test for AChR-Ab . However, its
progressive nature and the presence of hyperreflexia with Babinski signs can usually
distinguish ALS from myasthenia. (See "Amyotrophic lateral sclerosis")
Lambert-Eaton myasthenic syndrome — The Lambert-Eaton myasthenic
syndrome shares the same pathologic site with myasthenia gravis (the
neuromuscular junction) and has a similar pathophysiology (an autoimmune disease
usually associated with malignancy). However, the clinical presentation is markedly
different in the Lambert-Eaton syndrome . Hip girdle weakness is typically an
early symptom, making it difficult for the patient to rise from a chair or to climb
stairs. Less dramatic shoulder girdle weakness eventually occurs. Involvement of the
bulbar muscles or diplopia is rare, but ptosis is frequently seen.
In addition to the differences in muscle distribution, there are several other
differences between the Lambert-Eaton syndrome and myasthenia gravis :
Symptoms in the Lambert-Eaton syndrome are more likely to be present in the
morning and to improve during the day and with exercise.
Autonomic dysfunction, consisting of erectile impotence in men or dry mouth, is a
frequent finding in the Lambert-Eaton syndrome.
Repetitive nerve stimulation at high rates (20 to 50 cycles per second) produces
an increase in response, in contrast to the progressive weakness in myasthenia.
Approximately 70 percent of patients have cancer, usually small cell lung cancer.
The Lambert-Eaton syndrome is associated with unique autoantibodies. Over 95
percent of patients have antibodies against P/Q-type calcium channels; in
comparison, less than 5 percent of patients with myasthenia have such antibodies
. (See "Paraneoplastic syndromes of the nervous system", section on Lambert-
Eaton myasthenic syndrome).
Occasional patients with LEMS have AChR-Ab . Distinction from myasthenia
gravis in this setting is made by the usual presence of small cell lung cancer and
antibodies directed against the P/Q type calcium channels .
Botulism — Botulism can be confused with myasthenia because it affects the bulbar
and eye muscles; the most frequently occurring botulinum toxin, for example,
produces pupillary paralysis. (See "Botulism"). It is distinguished by its rapid
progression and the usual association with ingestion of food contaminated by
Clostridium botulinum. Thus, botulism is likely to affect a group, not just an
individual. It also shows an increase in response during repetitive nerve stimulation,
similar to that seen in the Lambert-Eaton syndrome.
Penicillamine-induced myasthenia — Approximately 1 percent of patients treated
with penicillamine develop myasthenia gravis . Penicillamine-induced disease
shares many of the characteristics of primary myasthenia gravis. It often begins with
ocular manifestations and then progresses to generalized weakness; it is also
associated with elevated AChR-Ab titer, a positive Tensilon test, and a decremental
response on repetitive nerve stimulation. However, the diagnosis may be missed if a
symptom such as weakness or dyspnea is ascribed to some underlying disease, such
as rheumatoid arthritis or chronic lung disease .
Myasthenia induced by penicillamine resolves when the drug is withdrawn in the
majority of cases . However, resolution of myasthenia may be quite slow and, if
incomplete, treatment for myasthenia may be required . This phenomenon
should not be confused with exacerbation of myasthenia that can be produced by a
variety of drugs. (See "Treatment of myasthenia gravis").
Congenital myasthenic syndromes — There are several rare, congenital
myasthenic syndromes. They should be considered when there is a positive family
history, a lack of response to anticholinesterase drugs (with a negative Tensilon
test), and the absence of AChR-Ab .
Although these conditions are not immune-mediated, they are confused with
myasthenia gravis because they also involve dysfunction of the acetylcholine
mediated neuromuscular synaptic transmission. Presynaptic, synaptic and post
synaptic dysfunction can all lead to weakness in the neonate or infant. In some of
these disorders, mutations in the acetylcholine receptor subunits result in gated
channels that show either increased or reduced sensitivity to acetylcholine
stimulation [36,37]. Autosomal recessive inheritance of mutations in the enzyme
choline acetyltransferase are one cause of presynaptic dysfunction .
As noted in the introduction, transplacental passage of antibodies to the
neuromuscular junction may cause neonatal myasthenia. The presence of
autoantibodies in both mother and neonate help differentiate this disorder from
those due to mutations that lead to myasthenia in the neonate. Both disorders are
discussed in more detail separately. (See "Neuromuscular junction disorders in
RECOMMENDATIONS — The optimal approach to the diagnosis of myasthenia
gravis varies with the clinical setting. As an example, the Tensilon test permits quick
confirmation of the diagnosis in patients with the classical distribution of weakness
that can be shown to be fatigable in the office. Because of its specificity, AChR-Ab
testing should also be performed while EMG with repetitive stimulation may not be
necessary. However, all three tests should be done when the diagnosis is uncertain.
Important negative tests to exclude other diseases in the differential diagnosis of
myasthenia gravis are also indicated in this setting and should include thyroid
function tests, antinuclear antibody and rheumatoid factor titers. Once the diagnosis
of myasthenia gravis is established, a chest CT scan should be performed to exclude
an associated thymoma especially in the patient over 40.