eMedicine Specialties > Neurology > Neuromuscular Diseases

Myasthenia Gravis

Author: Aashit K Shah, MD, Associate Professor of Neurology, Wayne State University; Program Director, Clinical Neurophysiology Fellowship, Department of Neurology, Detroit Medical Center
Contributor Information and Disclosures

Updated: Jan 15, 2009

Introduction

Background

Myasthenia gravis (MG) is an acquired autoimmune disorder characterized clinically by weakness of skeletal muscles and fatigability on exertion. Thomas Willis reported the first clinical description in 1672.

Pathophysiology

The antibodies in myasthenia gravis are directed toward the acetylcholine receptor (AChR) at the neuromuscular junction (NMJ) of skeletal muscles.

In 1960, Strauss demonstrated the presence of antibodies to muscle striations in serum of patients suffering from myasthenia gravis, implicating autoimmunity as the pathophysiological process.¹ Patrick and Lindstrom established the autoimmune origin of the disease when rabbits they immunized with the Torpedo californica AChR became myasthenic.²

To understand myasthenia gravis, familiarity with normal anatomy and functioning of NMJ is necessary. The nerve terminal of the motor nerve enlarges at its end, which is called the bouton terminale (terminal bulb). It lies within a groove or indentation along the muscle fiber. The presynaptic membrane (nerve membrane), postsynaptic membrane (muscle membrane), and synaptic cleft (space between the 2 membranes) together constitute the NMJ.

The presynaptic terminal contains vesicles filled with acetylcholine (ACh). On arrival of a nerve action potential, 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 on the postsynaptic membrane.

AChR is a ligand-gated sodium channel that opens briefly upon binding ACh. This allows entry of sodium ions into the interior of the muscle cell, which results in partial depolarization of the postsynaptic membrane and generation of an excitatory postsynaptic potential (EPSP). If the number of open sodium channels reaches threshold, a self-propagating muscle action potential is generated in the postsynaptic membrane.

ACh molecules are hydrolyzed by the enzyme acetylcholinesterase (AChE), which is abundantly present at the neuromuscular junction. The surface area of the postsynaptic membrane is increased by infolding of the membrane adjacent to the nerve terminal (see Image 1). This enables the NMJ to utilize fully the ACh released. 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 consists of 5 subunits (2 alpha, and 1 each of beta, gamma, and delta), each of which is a membrane-spanning protein molecule. Homology of AChR subunits exists among different species, which suggests that these encoding genes have evolved from a common ancestral gene. The subunits are arranged in a circular fashion, forming a central opening that functions as an ion channel (see Image 2). When an ACh molecule binds to the AChR, the AChR undergoes a 3-dimensional conformational change that opens the channel and results in increased sodium conductance.

Immunogenic mechanisms play important roles in the pathophysiology of myasthenia gravis. Supporting clinical observations include the presence of associated autoimmune disorders in patients suffering from myasthenia gravis (eg, autoimmune thyroiditis, systemic lupus erythematosus, rheumatoid arthritis). Moreover, infants born to myasthenic mothers can develop a transient myasthenia-like syndrome. Patients with myasthenia gravis 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 myasthenia gravis. Experimental observations supporting an autoimmune etiology of myasthenia gravis include the following: Induction of a myasthenia-like syndrome in mice by injecting a large quantity of immunoglobulin G (IgG) from myasthenia gravis patients (ie, passive transfer experiments); demonstration of IgG and complement at the postsynaptic membrane in patients with myasthenia gravis; and induction of a myasthenia-like syndrome in rabbits immunized against AChR by injecting them with AChR isolated from T californica.

The exact mechanism of loss of immunologic tolerance to AChR, a self antigen, is not understood. Myasthenia gravis can be considered a B cell–mediated disease, as antibodies (a B cell product) against AChR are responsible for the disease. However, the importance of T cells in pathogenesis of myasthenia gravis 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 myasthenia gravis 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 AChR by anti-AChR antibody, 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; and decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic membrane, with resultant decrease in available surface area for insertion of newly synthesized AChRs.

Patients without anti-AChR antibodies are recognized as seronegative myasthenia gravis (SNMG). Many of these patients with SNMG have antibodies against muscle-specific kinase (MuSK). MuSK plays a critical role in postsynaptic differentiation and clustering of acetyl choline receptors. The patients with anti-MuSK antibodies are predominantly female, and respiratory and bulbar muscles are frequently involved. Another group has reported patients having prominent neck, shoulder, and respiratory weakness.^3,4

Frequency

United States

Myasthenia gravis is uncommon. Estimated annual incidence is 2 per 1,000,000.

Mortality/Morbidity

Recent advances in treatment and care of critically ill patients have resulted in marked decrease in the mortality rate. The rate is now 3-4%, with principal risk factors being age older than 40 years, short history of severe disease, and thymoma. Previously, the mortality rate was as high as 30-40%.

Sex

The female-to-male ratio is said classically to be 6:4, but as the population has aged, the incidence is now equal in males and females.

Age

Myasthenia gravis presents at any age. Female incidence peaks in the third decade of life, whereas male incidence peaks in the sixth or seventh decade. Mean age of onset is 28 years in females and 42 years in males.

Transient neonatal myasthenia gravis 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 of the infants born to myasthenic mothers possess anti-AChR antibodies at birth, yet only 10-20% develop neonatal myasthenia gravis. 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 myasthenia gravis; thus, lowering the maternal serum titer during the antenatal period by plasmapheresis may be useful.

Clinical

History

Myasthenia gravis is characterized by fluctuating weakness increased by exertion. Weakness increases during the day and improves with rest. Presentation and progression vary.

• Extraocular muscle (EOM) 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 myopathiclike proximal weakness greater than 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.⁵
  • On the other hand, symptoms may remain limited to the EOM and eyelid muscles for years.
  • Rarely, patients with severe, generalized weakness may not have associated ocular muscle weakness.
  • The disease remains ocular in only 16% of patients. About 87% of patients generalize 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.
• Intercurrent illness 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.
• The Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) formed a Task Force in May 1997 to address the need for universally accepted classifications, grading systems, and methods of analysis for patients undergoing therapy and for use in therapeutic research trials. Thus, MGFA Clinical Classification was created.⁶
  • 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 and/or axial muscles
    • 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
  • Class V
    • Defined by intubation, with or without mechanical ventilation, except when used during routine postoperative management.
    • The use of a feeding tube without intubation places the patient in class IVb.

Physical

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/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.
• Facial muscle weakness
  • Weakness of the facial muscles is almost always present.
  • Bilateral facial muscle weakness produces a mask-like 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 due to EOM weakness also may be present.
• Bulbar muscle weakness
  • Weakness of palatal muscles can result in a nasal twang to the voice and nasal regurgitation of food and 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 usually are affected more severely than neck extensors.
• Limb muscle weakness
  • 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. Triceps are more likely to be affected than 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
  • Such weakness may produce acute respiratory failure. This 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 due to hypoventilation.
  • Weak pharyngeal muscles may collapse the upper airway. Careful monitoring of respiratory status is necessary in the acute phase of myasthenia gravis.
    • Negative inspiratory force (NIF), vital capacity (VC), 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.
• Ocular muscle weakness
  • Typically, EOM weakness is asymmetric. The weakness usually affects more than 1 EOM 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 upgaze exacerbates the ptosis while closing the eyes for a short period improves it.
• Evidence of other coexisting autoimmune diseases
  • Myasthenia gravis is an autoimmune disorder, and other autoimmune diseases occur more frequently in patients with myasthenia gravis than in the general population.
  • Some autoimmune diseases that occur at higher frequency in patients with myasthenia gravis 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 myasthenia gravis. This is important because in patients with hyperthyroidism, weakness may not improve with treatment of myasthenia gravis alone.

Causes

• Myasthenia gravis is idiopathic in most patients.
• Penicillamine is known to induce various autoimmune disorders, including myasthenia gravis.
• AChR antibodies are present in about 90% of patients developing myasthenia gravis secondary to penicillamine exposure.
• Even in patients who do not develop clinical myasthenia, antibodies can be demonstrated in some cases.
• Various drugs can exacerbate symptoms of myasthenia gravis.
  • Antibiotics (eg, aminoglycosides, ciprofloxacin, erythromycin, ampicillin)
  • Beta-adrenergic receptor blocking agents (eg, propranolol, oxprenolol)
  • Lithium
  • Magnesium
  • Procainamide
  • Verapamil
  • Quinidine
  • Chloroquine
  • Prednisone
  • Timolol (ie, a topical beta-blocking agent used for glaucoma)
  • Anticholinergics (eg, trihexyphenidyl)
• Neuromuscular blocking agents, including vecuronium and curare, should be used cautiously in myasthenics to avoid prolonged neuromuscular blockade.

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