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Myesthenia Gravis

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Myasthenia Gravis (MG)

Definition and pathophysiology MG is an acquired autoimmune disorder of the neuromuscular junction caused by autoantibodies directed against the alpha-1 subunit of nicotinic postsynaptic acetylcholine receptors (AChR), most commonly targeting the "main immunogenic region" of the receptor. These antibodies bind the receptor, activate complement, and accelerate receptor destruction, causing a reduction in AChR density and degeneration of the postjunctional folds. The result is fatigable weakness that worsens with repetitive activity and improves with rest - Medical Physiology, p. 1661-1665. A smaller subset of patients instead have antibodies against muscle-specific kinase (MuSK) or LRP4, which affect receptor clustering rather than the receptor itself.
Epidemiology MG affects roughly 25-125 per million people and has a bimodal age distribution. Early-onset disease clusters in women in their 20s-30s (often with thymic hyperplasia); late-onset disease is more common in men in their 50s-60s (more often with thymoma) - Medical Physiology, p. 1661.
Clinical features
  • Fluctuating, fatigable weakness - worse with exertion and toward the end of the day, better with rest
  • Ocular involvement is the presenting feature in about half of patients (ptosis, diplopia) and remains isolated to extraocular muscles in roughly 20% ("ocular MG")
  • Bulbar involvement (dysarthria, dysphagia) occurs early in 6-30% of patients and eventually develops in most; dysphagia is a major precipitant of myasthenic crisis - Bradley and Daroff's Neurology in Clinical Practice, p. 1567-1569
  • Generalized limb weakness, typically proximal > distal
  • Respiratory muscle weakness in severe cases can progress to myasthenic crisis requiring ventilatory support
Diagnosis
  • Serology: anti-AChR antibodies (most patients with generalized disease); anti-MuSK or anti-LRP4 in seronegative AChR cases
  • Electrodiagnostics: repetitive nerve stimulation showing a decremental response; single-fiber EMG showing increased jitter (most sensitive test)
  • Edrophonium (Tensilon) test - largely historical now given serologic/electrodiagnostic accuracy
  • Chest CT/MRI to evaluate for thymoma, since thymic pathology (hyperplasia or tumor) is common
Treatment
  1. Symptomatic therapy - acetylcholinesterase inhibitors (pyridostigmine) enhance cholinergic transmission; dosing must be carefully titrated since overexposure can cause depolarizing (cholinergic) blockade - Medical Physiology, p. 1669
  2. Immunosuppression - corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, or methotrexate to blunt the autoimmune attack
  3. Thymectomy - recommended in AChR-antibody-positive patients, especially under 65, and in anyone with thymoma; leads to clinical improvement in about 75% of thymoma cases
  4. Targeted/biologic agents - anti-CD20 (rituximab), complement inhibitors (eculizumab, ravulizumab), and neonatal Fc receptor (FcRn) blockers (efgartigimod) for refractory generalized MG
  5. Acute exacerbations/crisis - IVIG or therapeutic plasma exchange for rapid antibody removal, used for crises or perioperative stabilization
Recent evidence and updates A 2025 Cochrane systematic review examined rituximab for MG (PMID: 40607605) - worth checking if you want details on its efficacy evidence, since B-cell depletion therapy is an active area of study. Separately, the FDA approved inebilizumab (Uplizna), a CD19 B-cell-targeted monoclonal antibody, in December 2025 for generalized MG in AChR- or MuSK-antibody-positive adults, reflecting continued expansion of targeted biologic options beyond the classical corticosteroid/thymectomy paradigm.
If you want, I can go deeper into any specific angle - pathophysiology and NMJ pharmacology, the diagnostic workup, the treatment algorithm/crisis management, or MG in pregnancy/pediatrics.
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