Myasthenia Gravis Disease Background

Introduction

Myasthenia gravis (MG) is an uncommon neurological disorder caused by autoantibodies against the acetylcholine receptor (AChR), against a receptor-associated protein, muscle-specific tyrosine kinase (MuSK-Ab), or occasionally to the low-density lipoprotein receptor-related protein 4 (LRP4).  

Epidemiology

Based on several studies, myasthenia gravis has an incidence rate of 1.7 to 21.3 cases per million people and a prevalence rate of 15 to 179 per million. Myasthenia gravis affects all ages but have a bimodal distribution based on sex and age. In younger patients, those younger than 40, females predominate. In the fifth decade of life, cases are equally distributed between males and females. After the age of 50, males are more commonly affected. 

Pathophysiology

Myasthenia gravis is a classic example of an antibody-mediated autoimmune disease, an example of a class II hypersensitivity reaction where immunoglobulin (Ig) autoantibodies react with intra or extracellular antigens thus leading to end-organ damage. Additionally, different subtypes of T cells and their cytokines also play important roles in the pathogenesis of myasthenia gravis. All these results in an antibody-mediated, T-cell dependent immunologic attack on the postsynaptic membrane of the neuromuscular junction, thus leading to abnormal neuromuscular transmission and clinical weakness.

In most cases, antibodies bind to the main immunogenic region of the α-subunit of the AChR. However, there are cases where some patients may be seronegative for AChR antibodies; these patients have antibodies directed against another target on the surface of the muscle membrane, the MuSK. Lastly, antibodies to LRP4, the agrin-binding receptor of the MuSK complex, are found in up to 50% of individuals with seronegative myasthenia gravis.

Like other autoimmune disorders, myasthenia gravis is associated with the loss of tolerance to self-antigens. T-lymphocyte tolerance to self-antigens is established in the thymus, and thymic abnormalities like thymic hyperplasia and even thymomas are present in myasthenia gravis. 

Myasthenia Gravis_Disease Background

Classification

Autoimmune Myasthenia Gravis

Acetylcholine Receptor Myasthenia Gravis (AChR-MG)

Achr-MG is noted to be the most common form of MG. It is characterized by muscle weakness that is more predominant in the limbs and neck extensor than in bulbar and neck flexor muscles. There is also prominent ptosis and external ocular muscle weakness. In long-standing disease, wasting of proximal limb and ocular muscles may occur (myasthenic myopathy). In 65% of patients, there is some form of thymus pathology, 15% have thymoma. The risk of recurrence is low with AchR-MG.

Muscle-Specific Tyrosine Kinase Myasthenia Gravis (MuSK-MG)

Compared to AChR-MG, MuSK-MG predominantly affects the bulbar and neck flexor muscles than the limb and neck extensor muscles. Patients with MuSK-MG only have less prominent ptosis and extraocular muscle weakness compared to AChR-MG. With this type of MG, there is noted early wasting of facial and tongue muscles. In 10% of patients, there is noted thymic hyperplasia, and unlike AChR-MG, patients with MuSK-MG have high risk of recurrent crisis.

Other Forms of Myasthenia Gravis

Ocular Myasthenia Gravis

In this type, the disease is confined to the weakness of ocular muscles.

Generalized Myasthenia Gravis

In generalized MG, the weakness affects muscles other than the ocular muscles, but may still have some form of ocular weakness. The disease can be mild, moderate, or severe, characterized by respiratory involvement.

Anti-Lipoprotein Receptor Protein 4 (LRP4) Myasthenia Gravis

Patients with anti-LRP4 MG tend to be younger, more often to be female, and have a milder disease. With this type, there appears to be no association with thymic pathology, particularly thymoma.

Myasthenic Crisis or Relapse  

Relapse occurs when a patient with a previously controlled disease deteriorates. A crisis is considered severe if there is a need of respiratory assistance. This may be caused by reduction or withdrawal of previous therapy. Relapse or crisis may be elicited by stress (eg infection, surgery, hormonal factors) or by the introduction of a new drug (eg beta-blocker).