Advances in the Treatment of Myasthenia Gravis

Nils Erik Gilhus

Disclosures

Future Neurology. 2012;7(6):701-708. 

In This Article

Pathogenesis

MG patients should always be diagnosed according to disease subgroup. The MG subgroups reflect pathogenesis as well as therapeutic considerations:

  • Early-onset generalized MG

  • Late-onset generalized MG

  • MG with thymoma

  • Ocular MG

  • Anti-MuSK MG

  • Anti-LRP4 MG

  • Autoantibody-negative MG

The distinction between early- and late-onset MG is usually set at a debut age of 50 years.[7] Regarding pathogenesis and therapeutic response, this age limit is far from sharp. Thymic hyperplasia, female gender, other autoimmune disorders and HLA-B8, -DR3 support the pathogenetic early-onset subgroup. Approximately 10–15% of all MG patients have a thymoma; 30% of all patients who have a thymoma develop MG at some stage.[8] In thymoma patients, MG represents a paraneoplastic disorder. Ocular signs and symptoms are typical for MG, and also in the initial phases of the disease. In a minority of patients, the disease remains purely ocular. Ocular MG is defined as MG with still only ocular symptoms after more than 2 years.[7]

Autoantibodies against molecules in the postsynaptic muscle membrane relevant for neuromuscular transmission are the hallmark for MG. 80% of patients with generalized MG symptoms have antibodies against AChR, 1–10% against MuSK and very few against LRP4.[9,10] Among the remaining patients, some have low-affinity and/or low-concentration antibodies against AChR or more rarely against MuSK; such antibodies are not detected by the standard diagnostic techniques.[11] Some have autoantibodies against yet undefined membrane molecules or epitopes, and a few probably have nonautoantibody-mediated disease.

The thymus plays an important pathogenetic role in AChR antibody-associated MG. Most patients, and especially those with early-onset MG, have an enlarged and hyperplastic thymus. All thymoma patients have AChR antibodies, and even some thymoma patients without overt MG symptoms have such antibodies.[12] Negative T-cell selection, crucial for discrimination between self and nonself, takes place in the thymus. Defunct intrathymic negative selection can lead to autoimmune disease. It is interesting that thymus pathology is specific for MG and is only rarely linked to other autoimmune disorders.[6–8] The autoimmune regulators has gained interest as a potentially important intrathymic molecule for MG pathogenesis.[13,14] Autoantibodies against cytoplasmic muscle proteins such as titin and ryanodine receptor are characteristic for thymoma MG and also for a subgroup of late-onset MG.[15]

The primary cause of MG is unknown, except for those with a thymoma. A virus infection either generally or within the thymus has been suspected but is not yet proven.[16–18] Genetic predisposition takes place, the influence of HLA genes being most pronounced,[19] but genes do not represent a major cause. Epigenetic causative factors have not been defined so far.

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