Medicine

Last updated on: November 18th, 2022

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Myasthenia Gravis

Introduction

Definition

Myasthenia gravis (MG) is an autoimmune disease characterized by the formation of autoantibodies against acetylcholine receptors (AChRs) in the postsynaptic muscle membrane of the neuromuscular junction around the body. Clinically, it manifests as fluctuating weakness and progressive muscle fatigue as time passes—e.g., by the end of the day. Ocular MG (OMG) often presents before generalized MG (GMG) affecting the rest of the body sets in.

Classification

Patients are grouped according to the presence and type of autoantibodies present (for the purpose of treatment), clinical symptoms, age at onset, and thymus pathology. Also, the Myasthenia Gravis Foundation of America classifies MG by the muscle groups affected and severity of disease. Briefly, class I involves any ocular muscle weakness with all other muscle strength being normal. Classes II to IV describe mild, moderate and severe muscle weakness affecting muscles other than the ocular muscles (axial, limb, oropharyngeal, respiratory), respectively. Class V is defined as needing intubation, with or without mechanical ventilation.

Epidemiology

Though MG can occur at any age, a bimodal distribution has been theorized to exist. This describes peaks around 40 years of age showing a female predominance (considered early onset disease), and another around 60-80 years of age which affects men at least as often as women (considered late onset disease). The incidence of MG is estimated to extend to 30 million people a year, with an estimated global prevalence around 180 million.

Pathogenesis

MG's pathogenesis is a multi-tiered process. Known as a type II hypersensitivity reaction where IgG antibodies are directed against cell surface antigens, MG involves an autoimmune process driven by the anti-AChR T helper cells' (Th1 subtype of CD 4+ T cells) recognition of AChR epitopes and subsequent induction of B cells to produce anti-AChR autoantibodies (AChR-Ab) against the receptor. Muscle-specific kinase autoantibodies (MuSK-Ab) and low density lipoprotein receptor-related protein 4 antibodies (LPR4-Ab) are also produced in MG.


Cumulatively, these autoantibodies interfere with cholinergic transmission between nerve terminals and muscle fibers at the NMJ causing the downregulation, destruction, blockage or cluster disruption of AChRs in the postsynaptic membrane. This results in the fluctuating muscle weakness and fatigability characteristic of MG.


MG can affect ocular, bulbar, respiratory, and limb muscles. Clinical presentations vary by the type of autoantibody present and presence or absence of a thymus. High levels of anti-AChR Th1 cells are present in the blood of MG patients, while T regulatory CD4+ T cells crucial for maintaining self-tolerance may be lower.

Juvenile MG (JMG)

JMG can occur in children, though it is very rare. It is defined as MG in children under the age of 18. Though it is clinically similar to adult MG, with many overlapping symptoms, differentials are broader and spontaneous remission rates are higher. Its management is similar to adult MG with a focus on early intervention.

Complications

Though few, disease complications with MG include, but are not exclusively limited to:

  1. Thyroid pathology: MG is often associated with autoimmune induced thyroid dysfunction, including hyper- and hypothyroidism. Once MG is diagnosed, thyroid function testing must be done to uncover and treat any thyroid function abnormalities.
  2. Myasthenic crisis: A myasthenic crisis occurs when a patient's respiratory muscles and function fail acutely, and artificial ventilation is required to sustain life. This can be triggered by infection, such as a lower respiratory tract infection, or can occur following treatment resistance. A myasthenic crisis is improved with edrophonium. It is classified as a cholinergic crisis when edrophonium does not cause improvement. A myasthenic crisis is an emergency.
  3. Treatment-refractory MG: A subset of patients with MG have been found to demonstrate treatment-resistant disease, specifically though not exclusively, patients with MuSK-Ab and those with thymomas. These patients appear to be less responsive to conventional treatment including cholinesterase inhibitors and immunosuppressive agents, as compared with AChR-Ab positive patients.

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