Myasthenia Gravis

Author: Aashit K Shah, MD, FAAN, FANA; Chief Editor: Nicholas Lorenzo, MD,
CPE more...

Updated: May 2, 2014

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 remissions
Weakness tends to spread from the ocular to facial to bulbar muscles and then to
truncal and limb muscles
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
Surgery
Immunization
Emotional stress
Menstruation
Intercurrent illness (eg, viral infection)
Medication (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium,
phenytoin, beta-blockers, 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 normal
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.

Diagnosis

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 antiAChR 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.

Management
Therapy for MG includes the following:

Anticholinesterase (AchE) inhibitors

Immunomodulating agents
Intravenous immune globulin (IVIg)
Plasmapheresis
Thymectomy

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

IVIg

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

Plasmapheresis

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

Thymectomy

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.

Background
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 followup care in cooperation with the primary care physician.

Anatomy
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 NMJs.
Adult AChR comprises 5 subunits (2 alpha, 1 beta, 1 gamma, and 1 delta), each of which is a
membrane-spanning 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 3dimensional conformational change that opens the channel.

Acetylcholine receptor. Note 5 subunits, each with 4 membranespanning 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 calcium-dependent 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.

Pathophysiology
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 rundown).
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 MG.
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.

Etiology
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 demonstrated.
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 HLADQw2 (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)
Lithium
Magnesium
Procainamide
Verapamil
Quinidine
Chloroquine
Prednisone
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 MG.

Epidemiology
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 1986.

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 antibodies.
Most infants born to myasthenic mothers possess anti-AChR antibodies at birth, yet only 1020% 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]

Prognosis
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 adenocarcinoma
1 each of basal cell skin cancer; lung, gastric, breast, and colon adenocarcinoma; and
renal cell cancer

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, beta-blockers, 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.
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]
Proceed to Clinical Presentation