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Practice Essentials

Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against acetylcholine
nicotinic postsynaptic receptors at the neuromuscular junction of skeletal muscles (see the image below). [1, 2] MG
is sometimes identified as having an ocular and generalized form, although one is not exclusive of the other
and the ocular form is considered an initial, milder form of illness that progresses to the more severe
generalized form in most but not all patients.

Normal neuromuscular junction showing a presynaptic terminal with a motor nerve

ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded
with several acetylcholine receptors.

Signs and symptoms

The presentation of MG has the following characteristics:

The usual initial complaint is a specific muscle weakness rather than generalized weakness
Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs during the
course of illness in 90%
The disease remains exclusively ocular in only 16% of patients
Rarely, patients have generalized weakness without ocular muscle weakness
Bulbar muscle weakness is also common, along with weakness of head extension and flexion
Limb weakness may be more severe proximally than distally
Isolated limb muscle weakness is the presenting symptom in fewer than 10% of patients
Weakness is typically least severe in the morning and worsens as the day progresses
Weakness is increased by exertion and alleviated by rest
Weakness progresses from mild to more severe over weeks or months, with exacerbations and
Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb
About 87% of patients have generalized disease within 13 months after onset
Less often, symptoms may remain limited to the extraocular and eyelid muscles for years
The following factors may trigger or worsen exacerbations:
Bright sunlight
Emotional stress
Intercurrent illness (eg, viral infection)
Medication (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, betablockers, procainamide, statins)
The Myasthenia Gravis Foundation of America Clinical Classification divides MG into 5 main classes and
several subclasses[3] :
Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is

Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness
of any severity
Class IIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of
oropharyngeal muscles
Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser
or equal involvement of limb, axial muscles, or both
Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle
weakness of any severity
Class IIIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of
oropharyngeal muscles
Class IIIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser
or equal involvement of limb, axial muscles, or both
Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle
weakness of any severity
Class IVa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of
oropharyngeal muscles
Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser
or equal involvement of limb, axial muscles, or both; use of a feeding tube without intubation
Class V: Defined by the need for intubation, with or without mechanical ventilation, except when used
during routine postoperative management
See Clinical Presentation for more detail.

The antiacetylcholine receptor (AChR) antibody test for diagnosing MG has the following characteristics:

High specificity (up to 100%[4] )

Positive in as many as 90% of patients who have generalized MG
Positive in only 50-70% of patients who have purely ocular MG
False-positive anti-AChR antibody test results have been reported in patients with the following:

Thymoma without MG
Lambert-Eaton myasthenic syndrome
Small cell lung cancer
Rheumatoid arthritis treated with penicillamine
1-3% of the population older than 70 years
Assays for the following antibodies may also be useful:

Antistriated muscle antibody (present in about 84% of patients with thymoma who are younger than
40 years)

Anti-MuSK antibody (present in about half of patients with negative results for anti-AChR antibody)

Antistriational antibody (present in almost all patients with thymoma and MG, as well as in half of MG
patients with onset of MG at 50 years or older)
Other studies are as follows:

Plain chest radiographs may identify a thymoma as an anterior mediastinal mass

Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all
cases of MG

In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass
lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG

Electrodiagnostic studies (repetitive nerve stimulation and single-fiber electromyography)

See Workup for more detail.

Therapy for MG includes the following:

Anticholinesterase (AchE) inhibitors

Immunomodulating agents
Intravenous immune globulin (IVIg)
AchE inhibitors

Initial treatment for mild MG

Pyridostigmine is used for maintenance therapy[5, 6]
Neostigmine is generally used only when pyridostigmine is unavailable
Corticosteroid therapy provides a short-term benefit
Azathioprine, usually after a dose of corticosteroids, is the mainstay of therapy for difficult cases
Cyclosporine A and occasionally methotrexate and cyclophosphamide are used for severe cases

Moderate or severe MG worsening into crisis (no value in mild disease) [7]
Elderly patients
Patients with complex comorbid diseases (eg, acute respiratory failure) [8]
Patients with severe weakness poorly controlled with other agents

Generally reserved for myasthenic crisis and refractory cases

Also effective in preparation for surgery
Improvement is noted in a couple of days, but does not last for more than 2 months
Can be used long-term on a regular weekly or monthly basis can be used if other treatments cannot
control the disease

The standard of care for all patients with thymoma and for patients aged 10-55 years without thymoma
but with generalized MG
Proposed as a first-line therapy in most patients with generalized myasthenia
In ocular MG, should be delayed at least 2 years to allow for spontaneous remission
Not recommended in patients with antibodies to muscle-specific kinase (MuSK)
Controversial in prepubescent patients and, to a lesser extent, patients older than 55 years
See Treatment and Medication for more detail.

Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against nicotinic
acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of the skeletal muscles. The
basic pathology is a reduction in the number of ACh receptors (AChRs) at the postsynaptic muscle membrane
brought about by an acquired autoimmune reaction producing anti-AChR antibodies.
The reduction in the number of AChRs results in a characteristic pattern of progressively reduced muscle
strength with repeated use and recovery of muscle strength after a period of rest. The ocular and bulbar
muscles are affected most commonly and most severely, but most patients also develop some degree of
fluctuating generalized weakness.[9] The most important aspect of MG in emergency situations is acute
worsening of weakness and diagnosis of myasthenic versus cholinergic crisis and its management.
MG is a treatable and, at times, curable neurologic disorder. Pharmacologic therapy includes anticholinesterase
medication and immunosuppressive agents, such as corticosteroids, azathioprine, cyclosporine,
plasmapheresis, and intravenous immune globulin (IVIg). Plasmapheresis and thymectomy are also employed
to treat MG. Thymectomy is an especially important option if a thymoma is present. Patients with MG require
close follow-up care in cooperation with the primary care physician.


In MG, autoantibodies (immunoglobulin G [IgG]) develop against ACh nicotinic postsynaptic receptors at the
NMJ of skeletal muscles.[1, 2] The reasons for this development are unknown, although it is clear that certain
genotypes are more susceptible.[10] To understand MG, it is necessary to be familiar with the normal anatomy
and functioning of the NMJ.
The nerve terminal of the motor nerve enlarges at its end to form the so-called bouton terminale, or terminal
bulb. This bulb lies within a groove or indentation along the muscle fiber. The presynaptic membrane (on the
nerve), postsynaptic membrane (on the muscle membrane), and the synaptic cleft (the space between the 2
membranes) together constitute the NMJ (see the image below).

Normal neuromuscular junction showing a presynaptic terminal with a motor nerve

ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded
with several acetylcholine receptors.

ACh molecules are hydrolyzed by the enzyme acetylcholinesterase (AChE), which is abundantly present at the
NMJ. The surface area of the postsynaptic membrane is increased by infolding of the membrane adjacent to
the nerve terminal. This increase in surface area enables the NMJ to utilize the ACh fully. AChRs are present in
small quantities over most of the muscle membrane surface but are concentrated heavily at the tips of the
Adult AChR comprises 5 subunits (2 alpha, 1 beta, 1 gamma, and 1 delta), each of which is a membranespanning protein molecule. These subunits are homologous across different species, suggesting that the
encoding genes evolved from a common ancestral gene. The subunits are arranged in a circle, forming a
central opening that acts as an ion channel (see the image below). When an ACh molecule binds to an AChR,
the AChR undergoes a 3-dimensional conformational change that opens the channel.

Acetylcholine receptor. Note 5 subunits, each with 4 membrane-spanning domains

forming a rosette with a central opening. The central opening acts as an ion channel.

The presynaptic terminal contains vesicles filled with ACh. When an action potential travels down a motor nerve
and reaches the nerve terminal, the contents of these vesicles are released into the synaptic cleft in a calciumdependent manner. The released ACh molecules diffuse across the synapse and bind to the AChRs at the
peaks of the folds on the postsynaptic membrane.
This binding causes the ion channels in the AChR to open briefly, allowing sodium ions into the interior of the
muscle cell and thereby bringing about partial depolarization of the postsynaptic membrane and generation of
an excitatory postsynaptic potential (EPSP). If the number of open sodium channels reaches a threshold value,
a self-propagating muscle action potential is generated in the postsynaptic membrane.

With every nerve impulse, the amount of ACh released by the presynaptic motor neuron normally decreases
because of a temporary depletion of the presynaptic ACh stores (a phenomenon referred to as presynaptic
In MG, there is a reduction in the number of AChRs available at the muscle endplate and flattening of the
postsynaptic folds. Consequently, even if a normal amount of ACh is released, fewer endplate potentials will be
produced, and they may fall below the threshold value for generation of an action potential. The end result of
this process is inefficient neuromuscular transmission.
Inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon
results in a progressive decrease in the amount of muscle fibers being activated by successive nerve fiber
impulses. This explains the fatigability seen in MG patients.
Patients become symptomatic once the number of AChRs is reduced to approximately 30% of normal. The
cholinergic receptors of smooth and cardiac muscle have a different antigenicity than skeletal muscle and
usually are not affected by the disease.
The decrease in the number of postsynaptic AChRs is believed to be due to an autoimmune process whereby
anti-AChR antibodies are produced and block the target receptors, cause an increase the turnover of the
receptors, and damage the postsynaptic membrane in a complement-mediated manner.
Clinical observations support the idea that immunogenic mechanisms play important roles in the
pathophysiology of MG. Such observations include the presence of associated autoimmune disorders (eg,
autoimmune thyroiditis, systemic lupus erythematosus [SLE], and rheumatoid arthritis [RA]) in patients with
Moreover, infants born to myasthenic mothers can develop a transient myasthenialike syndrome. Patients with
MG will have a therapeutic response to various immunomodulating therapies, including plasmapheresis,
corticosteroids, intravenous immunoglobulin (IVIg), other immunosuppressants, and thymectomy.
Anti-AChR antibody is found in approximately 80-90% of patients with MG. Experimental observations
supporting an autoimmune etiology of MG include the following:

Induction of a myasthenialike syndrome in mice by injecting a large quantity of immunoglobulin G (IgG)

from MG patients (ie, passive transfer experiments)

Demonstration of IgG and complement at the postsynaptic membrane in patients with MG

Induction of a myasthenialike syndrome in rabbits immunized against AChR by injecting them with
AChR isolated from Torpedo californica (the Pacific electric ray)
The exact mechanism of loss of immunologic tolerance to AChR, a self-antigen, is not understood. MG can be
considered a B cellmediated disease, in that it derives from antibodies (a B cell product) against AChR.
However, the importance of T cells in the pathogenesis of MG is becoming increasingly apparent. The thymus
is the central organ in T cellmediated immunity, and thymic abnormalities such as thymic hyperplasia or
thymoma are well recognized in myasthenic patients.
Antibody response in MG is polyclonal. In an individual patient, antibodies are composed of different
subclasses of IgG. In most instances, 1 antibody is directed against the main immunogenic region (MIR) on the
alpha subunit. The alpha subunit is also the site of ACh binding, though the binding site for ACh is not the same
as the MIR. Binding of AChR antibodies to AChR results in impairment of neuromuscular transmission in
several ways, including the following:

Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and
degradation of AChR molecules

Causing complement-mediated destruction of junctional folds of the postsynaptic membrane

Blocking the binding of ACh to AChR

Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic
membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs
Patients without anti-AChR antibodies are recognized as having seronegative MG (SNMG). Many patients with
SNMG have antibodies against muscle-specific kinase (MuSK). MuSK plays a critical role in postsynaptic

differentiation and clustering of AChRs. Patients with anti-MuSK antibodies are predominantly female, and
respiratory and bulbar muscles are frequently involved. Another group has reported patients who exhibit
prominent neck, shoulder, and respiratory weakness. [11, 12]
The role of the thymus in the pathogenesis of MG is not entirely clear, but 75% of patients with MG have some
degree of thymus abnormality (eg, hyperplasia or thymoma). Histopathologic studies have shown prominent
germinal centers. Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and
possess AChRs on their surface membrane. These cells may become antigenic and unleash an autoimmune
attack on the muscular endplate AChRs by molecular mimicry.
The question of why MG afflicts the extraocular muscles first and predominantly remains unanswered. The
answer probably has to do with the physiology and antigenicity of the muscles in question.

MG is idiopathic in most patients. Although the main cause behind its development remains speculative, the
end result is a derangement of immune system regulation. MG is clearly an autoimmune disease in which the
specific antibody has been characterized completely. In as many as 90% of generalized cases, IgG to AChR is
present.[13] Even in patients who do not develop clinical myasthenia, anti-AChR antibodies can sometimes be
Patients who are negative for anti-AChR antibodies may be seropositive for antibodies against MuSK. Muscle
biopsies in these patients show myopathic signs with prominent mitochondrial abnormalities, as opposed to the
neurogenic features and atrophy frequently found in MG patients positive for anti-AChR. The mitochondrial
impairment could explain the oculobulbar involvement in anti-MuSKpositive MG. [14]
Numerous findings have been associated with MG. For example, females and people with certain human
leukocyte antigen (HLA) types have a genetic predisposition to autoimmune diseases. The histocompatibility
complex profile includes HLA-B8, HLA-DRw3, and HLA-DQw2 (though these have not been shown to be
associated with the strictly ocular form of MG). Both SLE and RA may be associated with MG.
Sensitization to a foreign antigen that has cross-reactivity with the nicotinic ACh receptor has been proposed as
a cause of myasthenia gravis, but the triggering antigen has not yet been identified.
Various drugs may induce or exacerbate symptoms of MG, including the following:

Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and ampicillin)

Penicillamine - This can induce true myasthenia, with elevated anti-AChR antibody titers seen in 90%
of cases; however, the weakness is mild, and full recovery is achieved weeks to months after discontinuance
of the drug
Beta-adrenergic receptor blocking agents (eg, propranolol and oxprenolol)
Timolol (ie, a topical beta-blocking agent used for glaucoma)
Anticholinergics (eg, trihexyphenidyl)
Neuromuscular blocking agents (eg, vecuronium and curare) - These should be used cautiously in
myasthenic patients to avoid prolonged neuromuscular blockade
Nitrofurantoin has also been linked to the development of ocular MG in 1 case report; discontinuance of the
drug resulted in complete recovery.
Thymic abnormalities are common: Of patients with MG, 75% have thymic disease, 85% have thymic
hyperplasia, and 10-15% have thymoma. Extrathymic tumors may include small cell lung cancer and Hodgkin
disease.[15, 16] Hyperthyroidism is present in 3-8% of patients with MG and has a particular association with ocular

United States statistics
MG is uncommon. The estimated annual US incidence is 2 per 1,000,000. The prevalence of MG in the United
States ranges from 0.5 to 14.2 cases per 100,000 people. This figure has risen over the past 2 decades,
primarily because of the increased lifespan of patients with MG but also because of earlier diagnosis. [5]About
15-20% of patients will experience a myasthenic crisis. Three fourths of these patients experience their first
crisis within 2 years of diagnosis.[10]

International statistics
In the United Kingdom, the prevalence of MG is 15 cases per 100,000 population. In Croatia, it is 10 cases per
100,000. In Sardinia, Italy, the prevalence increased from 0.75 per 100,000 in 1958 to 4.5 cases per 100,000 in

Age-related demographics
MG can occur at any age. Female incidence peaks in the third decade of life, whereas male incidence peaks in
the sixth or seventh decade. The mean age of onset is 28 years in females and 42 years in males.
Transient neonatal MG occurs in infants of myasthenic mothers who acquire anti-AChR antibodies via placental
transfer of IgG. Some of these infants may suffer from transient neonatal myasthenia due to effects of these
Most infants born to myasthenic mothers possess anti-AChR antibodies at birth, yet only 10-20% develop
neonatal MG. This may be due to protective effects of alpha-fetoprotein, which inhibits binding of anti-AChR
antibody to AChR. High maternal serum levels of AChR antibody may increase the chance of neonatal MG;
thus, lowering the maternal serum titer during the antenatal period by means of plasmapheresis may be useful.

Sex-related demographics
Classically, the overall female-to-male ratio has been considered to be 3:2, with a female predominance in
younger adults (ie, patients aged 20-30 years) and a slight male predominance in older adults (ie, patients
older than 50 years).[5, 9] Studies show, however, that with increased life expectancy, males are coming to be
affected at the same rate as females. Ocular MG shows a male preponderance. The male-to-female ratio in
children with MG and another autoimmune condition is 1:5.

Race-related demographics
The onset of MG at a young age is slightly more common in Asians than in other races. [5]

Given current treatment, which combines cholinesterase inhibitors, immunosuppressive drugs, plasmapheresis,
immunotherapy, and supportive care in an intensive care unit (ICU) setting (when appropriate), most patients
with MG have a near-normal life span. Mortality is now 3-4%, with principal risk factors being age older than 40
years, short history of progressive disease, and thymoma; previously, it was as high as 30-40%. In most cases,
the term gravis is now a misnomer.
Morbidity results from intermittent impairment of muscle strength, which may cause aspiration, increased
incidence of pneumonia, falls, and even respiratory failure if not treated. [13] In addition, the medications used to
control the disease may produce adverse effects.
Today, the only feared condition arises when the weakness involves the respiratory muscles. Weakness might
become so severe as to require ventilatory assistance. Those patients are said to be in myasthenic crisis.
The disease frequently presents (40%) with only ocular symptoms. However, the extraocular almost always are
involved within the first year. Of patients who show only ocular involvement at the onset of MG, only 16% still
have exclusively ocular disease at the end of 2 years.
In patients with generalized weakness, the nadir of maximal weakness usually is reached within the first 3
years of the disease. As a result, half of the disease-related mortality also occurs during this period. Those who

survive the first 3 years of disease usually achieve a steady state or improve. Worsening of disease is
uncommon after 3 years.
Thymectomy results in complete remission of the disease in a number of patients. However, the prognosis is
highly variable, ranging from remission to death.
A retrospective study of 38 patients with MG indicates that the disease, particularly late-onset MG, is
associated with a high risk for cancers outside of the thymus, whether or not the patient also has, as is
common in MG, a thymoma.[15]Extrathymic neoplasms occurred in 12 of the study patients; all of these tumors
were solid and heterogeneous to their organ of origin. Some of the tumors were diagnosed before and some
after the patients were diagnosed with MG.
Altogether the tumors represented 9 different types of neoplasm, as follows:

2 each of squamous cell carcinoma of the mouth, invasive bladder cancer, and prostate

1 each of basal cell skin cancer; lung, gastric, breast, and colon adenocarcinoma; and renal cell
The only statistically significant variable among the patients was age, with the extrathymic tumors being found
only in patients over 50 years. None of the patients with these neoplasms had thyroid disease or an
autoimmune disease other than MG.

Patient Education
Educate patients to recognize and immediately report impending respiratory crisis. Intercurrent infection may
worsen symptoms of MG temporarily. Mild exacerbation of weakness is possible in hot weather.
The risk of congenital deformity (arthrogryposis multiplex) is increased in offspring of women with severe MG.
Neonates born to women with MG must be monitored for respiratory failure for 1-2 weeks after birth. Certain
immunosuppressant drugs have teratogenic potential. Discuss these aspects with women in reproductive years
before beginning therapy with these drugs.
Certain medications (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, betablockers, procainamide, and quinidine) may exacerbate symptoms of MG; many others have been associated
only rarely with exacerbation of MG. Patients should always consult a neurologist before starting any of these
Medications that induce the hepatic microsomal cytochrome P-450 system (eg, corticosteroids) may render oral
contraceptives less effective.
Statins may cause worsening of myasthenia without regard to type of MG or brand of statin. Worsening of
weakness can occur independent of myalgic syndrome and usually involves oculobulbar symptoms within 1-16
weeks of the initiation of statin treatment.[17]