Miastenia gravis

Myasthenia Gravis

Aashit K Shah, MD, FAAN, FANA, Professor of Neurology, Director, Comprehensive Epilepsy Program, Program Director, Clinical Neurophysiology Fellowship, Detroit Medical Center, Wayne State University School of Medicine

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. Myasthenia gravis 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.

Essential update: MG linked to higher risk of extrathymic cancer

A recent 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.

The investigators found that 12 of the study’s patients had an extrathymic neoplasm; 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.

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[4] :

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 anti–acetylcholine receptor (AChR) antibody test for diagnosing MG has the following characteristics:

High specificity (up to 100%[5] )

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:

Anti–striated 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)

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[6, 7]

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)

Elderly patients

Patients with complex comorbid diseases (eg, acute respiratory failure)

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

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.[10] 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.

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.[11] 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).

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 3-dimensional conformational change that opens the 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 cell–mediated 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 cell–mediated 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.[12, 13]

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.[14] 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-MuSK–positive MG.[15]

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)

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.[3, 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.[6] About 15-20% of patients will experience a myasthenic crisis. Three fourths of these patients experience their first crisis within 2 years of diagnosis.[11]

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 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).[10, 6] 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.

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.[14] 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.

Clínicas presentation

History

The presentation and progression of myasthenia gravis (MG) vary. The usual initial complaint is a specific muscle weakness rather than generalized muscle weakness. The severity of the weakness typically fluctuates over hours being least severe in the morning and worse as the day progresses; it is increased by exertion and alleviated by rest. The degree of weakness also varies over the course of weeks or months, with exacerbations and remissions.

Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs during the course of illness in 90%. Bulbar muscle weakness is also common, along with weakness of head extension and flexion. Weakness may involve limb musculature with a myopathylike proximal weakness that is greater than the distal muscle weakness. Isolated limb muscle weakness as the presenting symptom is rare and occurs in fewer than 10% of patients.

Patients progress from mild to more severe disease over weeks to months. Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb muscles.[18] On the other hand, symptoms may remain limited to the extraocular and eyelid muscles for years. Rarely, patients with severe, generalized weakness may not have associated ocular muscle weakness.

The disease remains exclusively ocular in only 16% of patients. About 87% of patients have generalized disease within 13 months after onset. In patients with generalized disease, the interval from onset to maximal weakness is less than 36 months in 83% of patients.

Exposure to bright sunlight, surgery, immunization, emotional stress, menstruation, and physical factors might trigger or worsen exacerbations. Intercurrent illness (eg, viral infection) or medication can exacerbate weakness, quickly precipitating a myasthenic crisis and rapid respiratory compromise.

Spontaneous remissions are rare. Long and complete remissions are even less common. Most remissions with treatment occur during the first 3 years of disease.

MGFA classification of myasthenia gravis

In May 1997, the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) formed a task force to address the need for universally accepted classifications, grading systems, and analytic methods for management of patients undergoing therapy and for use in therapeutic research trials. As a result, the MGFA Clinical Classification was created.[4] This classification divides MG into 5 main classes and several subclasses, as follows.

Class I MG is characterized by the following:

Any ocular muscle weakness

May have weakness of eye closure

All other muscle strength is normal

Class II MG is characterized by the following:

Mild weakness affecting other than ocular muscles

May also have ocular muscle weakness of any severity

Class IIb MG is characterized by the following:

Predominantly affecting oropharyngeal, respiratory muscles, or both

May also have lesser or equal involvement of limb, axial muscles, or both

Class III MG is characterized by the following:

Moderate weakness affecting other than ocular muscles

May also have ocular muscle weakness of any severity

Class IIIa MG is characterized by the following:

Predominantly affecting limb, axial muscles, or both

May also have lesser involvement of oropharyngeal muscles

Class IIIb MG is characterized by the following:

Predominantly affecting oropharyngeal, respiratory muscles, or both

May also have lesser or equal involvement of limb, axial muscles, or both

Class IV MG is characterized by the following:

Severe weakness affecting other than ocular muscles

May also have ocular muscle weakness of any severity

Class IVa MG is characterized by the following:

Predominantly affecting limb, axial muscles, or both

May also have lesser involvement of oropharyngeal muscles

Class IVb MG is characterized by the following:

Predominantly affecting oropharyngeal, respiratory muscles, or both

May also have lesser or equal involvement of limb, axial muscles, or both

Class V MG is characterized by the following:

Defined by intubation, with or without mechanical ventilation, except when used during routine postoperative management

Use of a feeding tube without intubation places the patient in class IVb

Physical Examination

Patients with MG can present with a wide range of signs and symptoms, depending on the severity of the disease.

Mild presentations may be associated with only subtle findings, such as ptosis, that are limited to bulbar muscles. Findings may not be apparent unless muscle weakness is provoked by repetitive or sustained use of the muscles involved. Recovery of strength is seen after a period of rest or with application of ice to the affected muscle. Conversely, increased ambient or core temperature may worsen muscle weakness.

Variability in weakness can be significant, and clearly demonstrable findings may be absent during examination. This may result in misdiagnosis (eg, functional disorder). The physician must determine strength carefully in various muscles and muscle groups to document severity and extent of the disease and to monitor the benefit of treatment.

Another important aspect of the physical examination is to recognize a patient in whom imminent respiratory failure is imminent. Difficulty breathing necessitates urgent or emergent evaluation and treatment.

Weakness can be present in a variety of different muscles and is usually proximal and symmetric. Sensory examination and deep tendon reflexes are normal.

Weakness of the facial muscles is almost always present. Bilateral facial muscle weakness produces a masklike face with ptosis and a horizontal smile. The eyebrows are furrowed to compensate for ptosis, and the sclerae below the limbi may be exposed secondary to weak lower lids. Mild proptosis attributable to extraocular muscle weakness also may be present.

Weakness of palatal muscles can result in a nasal twang to the voice and nasal regurgitation of food (especially liquids). Chewing may become difficult. Severe jaw weakness may cause the jaw to hang open (the patient may sit with a hand on the chin for support). Swallowing may become difficult, and aspiration may occur with fluids, giving rise to coughing or choking while drinking. Weakness of neck muscles is common, and neck flexors are usually affected more severely than neck extensors are.

Certain limb muscles are involved more commonly than others (eg, upper limb muscles are more likely to be involved than lower limb muscles). In the upper limbs, deltoids and extensors of the wrist and fingers are affected most. The triceps is more likely to be affected than the biceps. In the lower extremities, commonly involved muscles include hip flexors, quadriceps, and hamstrings, with involvement of foot dorsiflexors or plantar flexors less common.

Respiratory muscle weakness that produces acute respiratory failure is a true neuromuscular emergency, and immediate intubation may be necessary. Weakness of the intercostal muscles and the diaphragm may result in carbon dioxide retention as a result of hypoventilation. Respiratory failure usually occurs around the time of surgery (eg, after thymectomy) or during later stages of the disease. However, it can be a presenting feature in about 14-18% of patients with MG.[19]

Weak pharyngeal muscles may collapse the upper airway. Careful monitoring of respiratory status is necessary in the acute phase of MG. Negative inspiratory force, vital capacity, and tidal volume must be monitored carefully. Relying on pulse oximetry to monitor respiratory status can be dangerous. During the initial phase of neuromuscular hypoventilation, carbon dioxide is retained but arterial blood oxygenation is maintained. This can lull the physician into a false sense of security regarding a patient’s respiratory status.

Typically, extraocular muscle weakness is asymmetric. The weakness usually affects more than 1 extraocular muscle and is not limited to muscles innervated by a single cranial nerve; this is an important diagnostic clue. The weakness of lateral and medial recti may produce a pseudointernuclear ophthalmoplegia, described as limited adduction of 1 eye, with nystagmus of the abducting eye on attempted lateral gaze. The nystagmus becomes coarser on sustained lateral gaze as the medial rectus of the abducting eye fatigues.

Eyelid weakness results in ptosis. Patients may furrow their foreheads, using the frontalis muscle to compensate for this weakness. A sustained upward gaze exacerbates the ptosis; closing the eyes for a short period alleviates it.

Evidence of coexisting autoimmune diseases

MG is an autoimmune disorder, and other autoimmune diseases are known to occur more frequently in patients with MG than in the general population. Some autoimmune diseases that occur at higher frequency in MG patients are hyperthyroidism, rheumatoid arthritis, scleroderma, and lupus.

A thorough skin and joint examination may help diagnose any of these coexisting diseases. Tachycardia or exophthalmos point to possible hyperthyroidism, which may be present in up to 10-15% of patients with MG. This is important because in patients with hyperthyroidism, weakness may not improve if only the MG is treated.

Complications

Systemically, myasthenic crisis is the most dreadful complication. Aspiration pneumonia also may occur as a consequence of poor oropharyngeal muscle function. Cholinergic crisis may follow excessive treatment with cholinesterase inhibitors.

The most common severe complication of MG is respiratory failure, which often presents with the rapid deterioration of respiratory effort that ultimately results in apnea.

Pneumonia is a common complication in patients with MG and often is the cause of death in fatal cases. Community-acquired pneumonia often is more severe in patients with MG because of their marginal respiratory function, inability to cough effectively, and inability to maintain tachypnea for long periods.

Other types of pneumonia are more common in patients with MG because these patients have a higher risk of aspiration. MG patients are also in a relatively immunocompromised state because of immunosuppressive medications. Consequently, they are at risk for aspiration pneumonia with mixed aerobic and anaerobic organisms, as well as organisms associated with immunocompromise (eg, Pseudomonas, other gram-negative organisms, and fungi).

Hypoxemia and respiratory acidosis often render the patient somnolent or unresponsive, in which case a clear history may be difficult to obtain.

Differential Diagnoses

Amyotrophic Lateral Sclerosis

Basilar Artery Thrombosis

Brainstem Gliomas

Cavernous Sinus Syndromes

Dermatomyositis/Polymyositis

Lambert-Eaton Myasthenic Syndrome

Multiple Sclerosis

Myocardial Infarction

Pulmonary Embolism

Sarcoidosis and Neuropathy

Thyroid Disease

Tolosa-Hunt Syndrome

Laboratory Tests

Anti–acetylcholine receptor antibody

The anti–acetylcholine receptor (AChR) antibody (Ab) test is reliable for diagnosing autoimmune myasthenia gravis (MG). It is highly specific (as high as 100%, according to Padua et al).[5] Results are positive in as many as 90% of patients who have generalized MG but in only 50-70% of those who have only ocular MG; thus false negatives are common in cases of purely ocular MG.

False-positive anti-AChR Ab test results have been reported in cases of thymoma without MG and in patients with Lambert-Eaton myasthenic syndrome, small cell lung cancer, or rheumatoid arthritis treated with penicillamine, as well as in 1-3% of the population older than 70 years.

Tindall reported AChR Ab results and mean Ab titers in a group of patients with MG

These data suggest a trend toward higher Ab titers in more severe disease, though the titer does not predict severity in an individual patient. Changes in the anti-AChR titer correlate with long-term improvement induced by prednisone or azathioprine; the same changes are not observed consistently in patients who undergo thymectomy. However, this finding is not consistent, and serial Ab titers alone are not reliable. Accordingly, serial Ab titers by themselves are not clinically useful for judging a patient’s response.

Anti–striated muscle antibody

The anti–striated muscle (anti-SM) Ab test is also important in patients with MG. Anti-SM Ab is present in about 84% of patients with thymoma who are younger than 40 years and less often in those without thymoma. Thus, a positive test result should prompt a search for thymoma in patients younger than 40 years. In individuals older than 40 years, anti-SM Ab can be present without thymoma.

Anti-MuSK antibody

About half of the patients with negative results for anti-AChR Ab (seronegative MG) may have positive test results for antibody to muscle-specific kinase (MuSK), a receptor tyrosine kinase that is essential for neuromuscular junction development.[21] These patients may represent a distinct group of autoimmune MG, in that they show some collective characteristics that are different from those of anti-AChR–positive patients.[22]

Anti-MuSK–positive individuals tend to have more pronounced bulbar weakness and may have tongue and facial atrophy. They may have neck, shoulder and respiratory involvement without ocular weakness. They are also less likely to respond to acetylcholine esterase (AChE) inhibitors, and their symptoms may actually worsen with these medications.[23, 24]

Antistriational antibody

Serum from some patients with MG possesses antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections. These antibodies react with epitopes on the muscle protein titin and ryanodine receptors (RyR).

Almost all patients with thymoma and MG, as well as half of the late-onset MG patients (onset at 50 years or later), manifest a broad striational antibody response. Striational antibodies are rarely found in anti-AChR–negative patients. They can be used as prognostic determinants in MG; as in all subgroups of MG, higher antibody titers are associated with more severe disease.[25] Because of a frequent association with thymoma, the presence of titin/RyR antibodies should arouse a strong suspicion of thymoma in a young patient with MG.

Other laboratory studies

Testing for rheumatoid factor and antinuclear antibodies (ANAs) is indicated to rule out systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Thyroid function tests are indicated to rule out associated Graves disease or hyperthyroidism. This is essential, especially in patients with ocular MG where the concomitant hyperthyroidism is most frequent.

Radiography, CT, and MRI

On plain anteroposterior and lateral views, radiography may identify a thymoma as an anterior mediastinal mass. A negative chest radiograph does not rule out a smaller thymoma, in which case a chest computed tomography (CT) scan is required. Chest CT scan should be obtained to identify or rule out thymoma or thymic enlargement in all cases of MG (see the images below). This is especially true in older individuals.

It is essential to rule out mass lesions compressing the cranial nerves in strictly ocular MG. CT or preferably magnetic resonance imaging (MRI) of the brain and orbit is indicated. It is helpful when the diagnosis of MG is not established and to rule out other causes of cranial nerve deficits. MRI can evaluate for intraorbital or intracranial lesions, basal meningeal pathology, or multiple sclerosis.

Electrodiagnostic Studies

Electrodiagnostic studies can demonstrate a defect of neuromuscular transmission. The following 2 studies are commonly performed:

Repetitive stimulation of a muscle at 2-3 Hz, also known as repetitive nerve stimulation (RNS)

Single-fiber electromyography (SFEMG), aimed at evaluating neuromuscular block, jitter, and fiber density

SFEMG is more sensitive than RNS in assessing MG. However, SFEMG is technically more difficult and much more dependent on the experience and skill of the testing physician. Consequently, RNS is the most frequently performed neurophysiologic test of neuromuscular transmission.

Repetitive nerve stimulation

During low-frequency (1-5 Hz) RNS, the locally available acetylcholine (ACh) becomes depleted at all neuromuscular junctions (NMJs), and less is therefore available for immediate release. This results in smaller excitatory postsynaptic potentials (EPSPs).

In patients without MG, all EPSPs exceed the threshold to generate an action potential (ie, there is a safety factor). No change in the summated compound muscle action potential (CMAP) is noted. In patients with MG, the number of AChRs is reduced, lowering the safety factor. During RNS, some EPSPs may not reach threshold, which means that no action potential is generated. This results in the decrement in the amplitude of the CMAP.

In patients with myasthenia gravis, this decremental response usually has a maximum decrement at the fourth or fifth response, followed by a tendency toward repair (see the images below). A stimulation rate of 1-5 per second should result in a 10% or more decrease in amplitude by the fourth or fifth action potential; any decrement over 10% is considered abnormal. The most common employed stimulation rate is 3 Hz.

Patients with MG rarely have a decreased response in a clinically normal muscle. Thus, testing a proximal weak muscle gives a better yield than testing a unaffected distal muscle, even if the latter is technically easier. Testing a facial muscle (eg, the orbicularis oculi) is useful because most patients suffer from eyelid weakness or ptosis. RNS results are less likely to be positive in patients with ocular MG.

Factors affecting results

Several factors can affect RNS results. Lower temperatures increase the amplitude of the CMAPs. Patients with MG may report clinically significant improvement in cold temperatures, and they typically report worsening of ptosis in bright sunlight or on a warm day. Therefore, maintaining a constant and perhaps higher-than-ambient temperature during RNS testing is important to bring out abnormalities of NMJ function. The temperature of the skin overlying the tested muscle should be at least 34°C.

Administration of AChE inhibitors before testing may mask the abnormality and consequently should be avoided for at least 1 day beforehand (even longer for long-acting agents).

Factors related to tetanic contraction may also affect RNS findings. A tetanic contraction of muscle is followed by 2 distinct phases:

Posttetanic potentiation, occurring for the first 2 minutes after tetanic contraction

Posttetanic exhaustion, lasting an additional 15 minutes after posttetanic potentiation

During posttetanic potentiation, accumulation of calcium inside the terminal axon causes enhanced mobilization and release of ACh, which overcomes the reduced number of AChRs at the NMJ and thus leads to larger EPSPs with additional recruitment of muscle fibers, resulting in a larger CMAP. In MG, this potentiation may normalize RNS results.

In the posttetanic exhaustion phase, the NMJ is less excitable, and even fewer EPSPs reach threshold. Thus, some patients with an equivocal abnormality on RNS during the resting phase may show clear-cut abnormalities during the posttetanic exhaustion phase.

Tetanic contraction of the muscle can be achieved by applying electrical stimulation to the nerve at a rate of 50 per second for 20-30 seconds. However, this is painful. Voluntary contraction of the muscle for 10 seconds at the maximum force can achieve the same goal without discomfort and is preferred.

Single-fiber electromyography

A concentric needle electrode and other monopolar and bipolar needle electrodes can record single motor unit potentials, but they cannot discriminate individual muscle fibers within the motor unit. The single-fiber needle used in SFEMG, which has a small recording surface, allows recording from individual muscle fibers.

SFEMG is capable of determining jitter (ie, variability of the time interval between the action potentials of 2 single muscle fibers in the same motor unit) and fiber density (ie, number of single-fiber action potentials within recording radius of the needle). Increased jitter (with or without impulse blocking) and normal fiber density are suggestive of a neuromuscular fiber transmission defect (see the image below).

Examination of a weak muscle with SFEMG is more useful than examination with RNS in demonstrating abnormal neuromuscular transmission. SFEMG of the extensor digiti communis (EDC) yields abnormal results in 87% of patients with generalized MG. Examination of a second muscle raises the sensitivity to 99%. In ocular MG, examination of the frontalis is more useful than examination of the EDC. Frontalis findings are abnormal in almost 100% of patients, but only about 60% of EDC findings are abnormal.

Treatment with AChR inhibitors does not normalize SFEMG results. SFEMG findings are abnormal in almost 100% of patients, whereas RNS findings are abnormal in only 44-65%. SFEMG is a good substitute for RNS in patients with ocular MG; a study by Padua et al on 86 patients with ocular MG showed 100% sensitivity.[5] However, SFEMG is technically demanding and highly operator-dependent. In addition, it has a lower specificity, and it can give positive results in other neuromuscular disorders.

Anticholinesterase Test

In patients with MG, the number of AChRs at the NMJ is low, which results in a decreased number of interactions between ACh and its receptor. ACh released from motor nerve terminals is metabolized by AChE. As a result, pharmacologic inhibition of AChE increases ACh concentration at the NMJ, improving the chance for interactions between ACh and its receptor. Edrophonium is a short-acting AChE inhibitor that improves muscle weakness in patients with MG.

This test evaluates weakness (eg, ptosis, partial or complete ophthalmoplegia, and forced hand grip) in an involved group of muscles before and after intravenous (IV) administration of edrophonium. Blinding of both the examiner and the patient increases the validity of the test.

To perform the test, a test dose of 0.1 mL of 10 mg/mL edrophonium solution is administered. If no response and no untoward effects are noted, remainder of the drug (0.9 mL) is injected. Sinus bradycardia due to excessive cholinergic stimulation of the heart is a serious complication; consequently, an ampule of atropine should be available at the bedside or in the clinic room while the test is performed.

This test may give both false-negative results and false-positive results. It has a low sensitivity in ocular MG; 50% of patients presenting with eye symptoms will be missed. On the other hand, diseases other than MG, such as amyotrophic lateral sclerosis (ALS) and cavernous sinus lesions can score positive on the test.[26] This test has been combined with electromyography (EMG) and ocular tonography to increase its sensitivity in ocular MG; however, it still produces false-negative and false-positive results.

Edrophonium is being used in combination with the Lancaster red-green screen testing for diplopia. Most patients would show an improvement in some fields of gaze and a worsening in other directions of gaze. Other patients would not appreciate any change.

The combination of edrophonium with electronystagmographic analysis of optokinetic nystagmus, seems promising for the diagnosis of ocular MG.[27, 28]

Ice Pack Test

The ice pack test (ie, placing ice over the lid) has gained interest among ophthalmologists for assessing improvement in ptosis and diplopia in ocular MG. The rationale behind this test is that cooling might improve neuromuscular transmission.

Movaghar and Slavin questioned the validity of such a test by demonstrating that patients with ocular MG actually improve on the ice, heat, and modified sleep tests.[29] Hence, rest might be the cause of the improvement in ocular signs. Both the ice test and the rest test are sensitive and specific in ocular MG.[30]

Histologic Findings

Studies of muscle biopsy specimens showed that the NMJs of patients with MG had only one third as many AChRs as average normal individuals. Morphologic changes, such as simplification of the pattern of postsynaptic membrane folding and an increase in the gap between the nerve terminal and the postsynaptic muscle membrane, also are present.

Lymphofollicular hyperplasia of thymic medulla occurs in 65% of patients with MG and thymoma occurs in 15%.

Treatment And management

Approach Considerations

Even though no rigorously tested treatment trials have been reported and no clear consensus exists on treatment strategies, myasthenia gravis (MG) is one of the most treatable neurologic disorders. Several factors (eg, severity, distribution, rapidity of disease progression) should be considered before therapy is initiated or changed.

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. They are not traditional medical immunomodulating therapies, but they function by modifying the immune system. Thymectomy is an important treatment option for MG, especially if a thymoma is present. A cardiothoracic surgeon should be consulted whenever thymectomy is contemplated as part of treatment.

MG is a chronic disease that may worsen acutely over days or weeks (and on rare occasions, over hours). Treatment requires scheduled reevaluation and a close doctor-patient relationship. Patients with MG require close follow-up care in cooperation with the primary care physician.

Intubation and intensive care unit (ICU) transfer usually are reserved for patients in myasthenic crisis with respiratory failure. Rapid respiratory failure may occur if the patient is not monitored properly. Patients should be watched very carefully, especially during exacerbation, by measuring negative inspiratory force and vital capacity.

Pharmacologic Therapy

Acetylcholine esterase (AChE) inhibitors and immunomodulating therapies are the mainstays of treatment.

In the mild form of the disease, AChE inhibitors are used initially. These agents include pyridostigmine, neostigmine, and edrophonium. Pyridostigmine is used for maintenance therapy.[6, 7] Neostigmine is generally used only when pyridostigmine is unavailable. Edrophonium is primarily used as a diagnostic tool to predict the response to longer-acting cholinesterase inhibitors (see Workup).[31]

With AChE inhibitors, a wide variability exists in the effective dose, depending on the severity and current activity of the disease and the presence of other factors that influence cholinergic transmission (eg, certain antibiotics, antidysrhythmic medications, and impaired renal function).[32, 7] Most patients are able to titrate the dosage of their medication to control disease symptoms, but severe exacerbations can occur in patients with previously well-controlled disease.[7]

Most patients with generalized MG require additional immunomodulating therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids.

The corticosteroid regimen should be tailored according to the patient’s overall improvement. The lowest effective dose should be used on a long-term basis. Because of the delayed onset of effects, steroids are not recommended for routine use in the emergency department (ED). Patients who are taking long-term moderate or high doses of steroids may have suppressed adrenal function and may require stress doses (eg, hydrocortisone 100 mg IV in an adult) during acute exacerbations.[7]

Limited evidence from randomized, controlled trials (RCTs) suggests that corticosteroid therapy provides a short-term benefit in MG; this supports the conclusions of previous observational studies, as well as expert opinion. A systematic review found no clear difference between steroids and IVIg or azathioprine; however, further trials are indicated because of the flaws in the trials reviewed.[33]

Other medications that are used to treat more difficult cases include azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly.[34, 35, 36]

The mainstay of therapy is still azathioprine, usually after an initial dose of corticosteroids. Cyclosporine A and occasionally methotrexate and cyclophosphamide are used for severe cases, while tacrolimus is under investigation.[37] No evidence-based studies fully prove the usefulness of AChE inhibitors, corticosteroids, and other immunosuppressive agents in improving ocular symptoms. In addition, the effect of corticosteroids and azathioprine on the progression to generalized MG is still uncertain.[38]

To date, most of the studies on immunomodulatory therapy have had few participants and have found it difficult to assess the efficacy of the addition of immunosuppressive therapy to the previous regimens of corticosteroids and AChE inhibitors. Furthermore, most of the RCTs were short-term and did not evaluate long-term usage of these drugs. As a result, good RCT data on the use of immunosuppressive agents as monotherapy or dual therapy with steroids are absent.[39]

However, limited evidence indicates that cyclosporine and cyclophosphamide improve symptoms in MG and decrease the amount of corticosteroid usage. The more common drugs used in MG, such as azathioprine and tacrolimus, show no clear benefit in use.[39]

IVIg is a more cost-effective and clinically superior alternative to plasmapheresis (see Plasmapheresis below). It appears to be a better treatment option for the elderly and those with complex comorbid diseases, such as acute respiratory failure.[9] IVIg is recommended for MG crisis, in patients with severe weakness poorly controlled with other agents, or in lieu of plasma exchange at a dose of 1 g/kg.[14, 40, 41]

IVIg is effective in moderate or severe MG worsening into crisis, but it does not exhibit value in mild disease.[8] Studies reveal that patients who have moderate or severe MG (ie, who are not in crisis) do not show an improvement in function or a reduced need for steroids.[14] Data neither support or rule out a role for IVIg in chronic MG.[14] To be included in IVIg studies, patients have been required to be autoantibody-positive. Therefore, the use of IVIg in a seronegative patient is not supported by the literature.[14]

Management of neonatal myasthenia gravis

Transient neonatal MG, in which MG is transmitted vertically from an affected mother to her fetus, occurs in 10-30% of neonates born to myasthenic mothers. It may occur any time during the first 7-10 days of life, and infants should be monitored closely for any signs of respiratory distress.

The syndrome of neonatal myasthenia is caused by transplacental transfer of maternal autoantibodies against the acetylcholine receptor (AChR). Infants affected by this condition are floppy at birth, and they display poor sucking, muscle tone, and respiratory effort. They often require respiratory support and intravenous (IV) feeding, as well as monitoring in a neonatal ICU. As the transferred maternal antibodies are metabolized over several weeks, symptoms abate and the infants develop normally.

Treatment with cholinesterase inhibitors is effective in this age group as well. However, the dosage must be carefully titrated to the clinical effect.

Complications

Long-term immunomodulating therapies may predispose patients with MG to various complications. Long-term steroid use may cause or aggravate osteoporosis, cataracts, hyperglycemia, weight gain, avascular necrosis of hip, hypertension, opportunistic infection, and other complications. Long-term steroid use also increases the risk of gastritis or peptic ulcer disease. Patients on such therapy should take an H2 -blocker or antacid as well.

Some complications are common to any immunomodulating therapy, especially if the patient is on more than 1 agent. These would include infections such as tuberculosis, systemic fungal infections, and Pneumocystis carinii pneumonia. The risk of lymphoproliferative malignancies may be increased with chronic immunosuppression. Immunosuppressive drugs may have teratogenic effects.

Initial deterioration in weakness before improvement is a common and serious concern within the first 3 weeks of immunomodulatory therapy; this potential complication warrants initiation of high doses in a supervised setting.

Excessive use of cholinesterase inhibitors can result in a cholinergic crisis. Other immunosuppressive medications increase the incidence of opportunistic infections, renal insufficiency, and hypertension.

Thymectomy

Even though no controlled trial to assess the efficacy of thymectomy in MG has been reported, this procedure has become the standard of care and is indicated for all patients with thymoma and for patients aged 10-55 years without thymoma but with generalized MG. Thymectomy has been proposed as a first-line therapy in most patients with generalized myasthenia. Research is under way to determine whether thymectomy combined with prednisone therapy is more beneficial in treating nonthymomatous MG than prednisone therapy alone.

In ocular MG, thymectomy should be delayed at least 2 years to allow for spontaneous remission or the development of generalized MG. Whether thymectomy is to be performed for prepubescent patients or patients older than 55 years is still controversial. Reports tend to encourage surgical treatment for the latter group.

Thymectomy is not recommended in patients with antibodies to muscle-specific kinase (MuSK), because of the typical thymus pathology, which is very different from the more common type of MG characterized by seropositivity for AChR antibodies.[42]

Patients often experience some transient worsening of symptoms early in the postoperative period. Improvement usually is delayed for months or years. Complete removal of thymic tissue is widely considered to be of the utmost importance, on the grounds that any small remnant might lead to recurrence.

Thymectomy may induce remission. This occurs more frequently in young patients with a short duration of disease, hyperplastic thymus, more severe symptoms, and a high antibody titer, although a high titer of antibody is not consistently linked to better outcome.[43]

Remission rate increases with time: at 7-10 years after surgery, it reaches 40-60% in all categories of patients except those with thymoma. In the absence of a thymoma, 85% of patients experience improvement, and 35% of these patients achieve drug-free remission. In a study by Nieto et al, the rate of remission in the presence of thymic hyperplasia was 42% compared to 18% in patients with thymoma.[44]

Robotic thymectomy

A robotic minimally invasive approach to thymectomy has been used.[45] In a review of 100 consecutive patients who underwent left-sided robotic thymectomy for MG, Marulli et al demonstrated the safety and efficacy of this procedure. No deaths or intraoperative complications occurred. On 5-year clinical follow-up, 28.5% of patients had complete stable remission, and 87.5% showed overall improvement. Remission was significantly more likely in patients with preoperative Myasthenia Gravis Foundation of America class I to II MG.[46]

MGFA classification of thymectomy

Over the years, many different techniques have been employed to perform thymectomy. Although it is generally believed that complete removal of thymic tissue is better (see above), this is not an established fact. There is no consensus as to whether one technique is superior to another in achieving benefit or minimizing risks.

The Myasthenia Gravis Foundation of America (MGFA) has proposed a classification scheme for thymectomy, which is primarily based on techniques described in various published reports.[4]

The MGFA thymectomy classification is as follows:

T-1 transcervical thymectomy – Basic; extended

T-2 videoscopic thymectomy - Classic or VATS (video-assisted thoracic surgery) thymectomy; VATET (video-assisted thoracoscopic extended thymectomy)

T-3 transsternal thymectomy – Standard; extended

T-4 transcervical and transsternal thymectomy

Diet and Activity

Patients with MG may experience difficulty chewing and swallowing because of oropharyngeal weakness. It may be difficult for the patient to chew meat or vegetables because of masticatory muscle weakness. If dysphagia develops, it is usually most severe for thin liquids because of weakness of pharyngeal muscles. To avoid nasal regurgitation or frank aspiration, liquids should be thickened.

Educate patients about the fluctuating nature of weakness and exercise-induced fatigability. Patients should be as active as possible but should rest frequently and avoid sustained physical activity.

Medication Summary

Acetylcholine esterase (AChE) inhibitors are considered to be the basic treatment of myasthenia gravis (MG). Edrophonium is primarily used as a diagnostic tool owing to its short half-life. Pyridostigmine is used for long-term maintenance.

High doses of corticosteroids commonly are used to suppress autoimmunity. Patients with MG also may be taking other immunosuppressive drugs (eg, azathioprine or cyclosporine). Adverse effects of these medications must be considered in assessment of the clinical picture. Bronchodilators may be useful in overcoming the bronchospasm associated with a cholinergic crisis.