Myasthenia gravis: Newer therapies offer sustained improvement

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ABSTRACTMyasthenia gravis is a prototypical antibody-mediated autoimmune neuromuscular disorder. Treatments have improved over the past 30 years, leading to significantly fewer deaths and better quality of life. Future research should further elucidate its pathogenesis, reveal better ways to diagnose it, and yield new treatments.


  • In most cases of myasthenia gravis, the patient has antibodies against acetylcholine receptor (AChR) or musclespecific tyrosine kinase (MuSK).
  • Myasthenia gravis is diagnosed by clinical signs, bedside tests (the ice-pack test or the edrophonium test), serologic tests for AChR antibodies or MuSK antibodies, and electrophysiologic tests.
  • Acetylcholinesterase inhibitors are the first-step therapy, but patients who have moderate to severe symptoms require some form of immunomodulating therapy.
  • A number of drugs can exacerbate weakness in myasthenia gravis and should be avoided or used with caution. These include penicillamine, interferons, procainamide, quinidine, and antibiotics such as quinolones and aminoglycosides.



Current therapies for myasthenia gravis can help most patients achieve sustained improvement. The overall prognosis has dramatically improved over the last 4 decades: the mortality rate used to be 75%; now it is 4.5%.1

Myasthenia gravis is the most common disorder of neuromuscular junction transmission and is also one of the best characterized autoimmune diseases. However, its symptoms—primarily weakness—vary from patient to patient, and in the same patient, by time of day and over longer time periods. The variation in symptoms can be very confusing to undiagnosed patients and puzzling to unsuspecting physicians. Such diagnostic uncertainty can give the patient additional frustration and emotional stress, which in turn exacerbate his or her condition.

In this review, we will give an overview of the pathogenesis, clinical manifestations, diagnosis, and treatment of myasthenia gravis.


The annual incidence of myasthenia gravis is approximately 10 to 20 new cases per million, with a prevalence of about 150 to 200 per million.2

The age of onset has a bimodal distribution, with an early incidence peak in the second to third decade with a female predominance and a late peak in the 6th to the 8th decade with a male predominance.2

Myasthenia gravis is commonly associated with several other autoimmune disorders, including hypothyroidism, hyperthyroidism, systemic lupus erythematosus, rheumatoid arthritis, vitiligo, diabetes, and, more recently recognized, neuromyelitis optica.3


Figure 1.

In most cases of myasthenia gravis the patient has autoimmune antibodies against constituents of the neuromuscular junction, specifically acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) (Figure 1).

AChR antibody-positive myasthenia gravis

When antibodies bind to AChR on the postsynaptic membrane, they cross-link neighboring AChR units, which are absorbed into the muscle fiber and are broken up.4 In addition, the complement system is activated to mediate further damage on the postsynaptic membrane.

AChR antibodies may come from germinal centers of the thymus, where clustered myoid cells express AChR on the plasma membrane surface.5 About 60% of AChR antibody-positive myasthenia gravis patients have an enlarged thymus, and 10% have a thymoma—a tumor of the epithelial cells of this organ. Conversely, about 15% of patients with a thymoma have clinical myasthenia gravis, and an additional 20% possess antibodies against AChR in the serum without myasthenic symptoms.5

MuSK antibody-positive myasthenia gravis

Like AChR, MuSK is a transmembrane component of the postsynaptic neuromuscular junction. During formation of the neuromuscular junction, MuSK is activated through the binding of agrin (a nerve-derived proteoglycan) to lipoprotein-related protein 4 (LRP4), after which complicated intracellular signaling promotes the assembly and stabilization of AChR.6

Unlike AChR antibodies, antibodies against MuSK do not activate the complement system, and complement fixation is not essential for clinical myasthenic symptoms to appear.7 Also, myasthenia gravis with MuSK antibodies is rarely associated with thymoma.8

The precise mechanism by which MuSK antibody impairs transmission at the neuromuscular junction has been a mystery until recently. Animal models, including MuSK-mutant mice and mice injected with MuSK protein or with purified immunoglobulin G from patients with this disease, have revealed a significant reduction of AChR clusters and destruction of neuromuscular junction structures.7,9–12

In addition, MuSK antibodies produce pre-synaptic dysfunction, manifesting as a reduction of acetylcholine content. This information is based on studies in mice and on in vitro electrophysiologic analyses of neuromuscular junctions from a patient with this disease.7,9–13

Finally, MuSK antibodies may indirectly affect the recycling of acetylcholine. After post-synaptic activation, acetylcholine is normally hydrolized by acetylcholinesterase, which is located in the synaptic cleft but anchored to MuSK on the postsynaptic membrane. MuSK antibodies block the binding of MuSK to acetylcholinesterase, possibly leading to less accumulation of acetylcholinesterase.14 This process may explain why patients with MuSK antibody-positive myasthenia gravis tend to respond poorly to acetylcholinesterase inhibitors (more about this below).


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