Myasthenia Gravis

Risk factors

• Female sex (younger onset)
• Thymic abnormalities: thymic hyperplasia (~65%, especially young women) or thymoma (~10-15%, especially older patients)
• Other autoimmune conditions: autoimmune thyroid disease, rheumatoid arthritis, lupus, type 1 diabetes
• Family history of autoimmunity

Pathophysiology

Anti-AChR antibodies block, cross-link (causing internalization), and complement-mediated destruction of postsynaptic AChRs at the neuromuscular junction. The result is reduced safety factor for neuromuscular transmission — repeated muscle use depletes available AChRs faster than they can be replaced, producing fatigability. MuSK antibodies disrupt clustering of AChRs. The thymus appears central to immune dysregulation in many patients.

Clinical presentation

Differential diagnosis

• Lambert-Eaton myasthenic syndrome (LEMS) — Voltage-gated calcium channel antibodies, proximal leg weakness improves briefly with exercise (post-exercise facilitation), absent reflexes return after exercise, associated with small cell lung cancer (~50%)
• Botulism — Descending paralysis, dilated pupils, dry mouth, food or wound exposure
• Guillain-Barré syndrome — Areflexia, ascending pattern, antecedent infection, CSF protein elevation
• Thyroid eye disease (Graves ophthalmopathy) — Proptosis, lid lag, restricted EOM from fibrosis, thyroid abnormality
• Mitochondrial myopathy (CPEO) — Progressive symmetric ophthalmoplegia without diplopia (slow progression so brain compensates), no fatigability
• Brainstem stroke or mass — Other neurologic findings, imaging
• Drug-induced myasthenia / unmasking — Aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, statins, immune checkpoint inhibitors

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• Myasthenic crisis (severe weakness with respiratory failure)
• Cholinergic crisis from excessive pyridostigmine — abdominal cramping, diarrhea, salivation, lacrimation, miosis, fasciculations
• Aspiration pneumonia
• Side effects of long-term steroids (osteoporosis, diabetes, weight gain, infection)
• Steroid-sparing agent toxicities (bone marrow suppression, hepatotoxicity)
• Thymoma-associated paraneoplastic syndromes
• Pregnancy: transient neonatal MG (transplacental antibodies) in ~10-15% of newborns of MG mothers

PANCE pearls

• Fatigability is the cardinal feature — symptoms worsen with use, improve with rest. Ask about end-of-day worsening.
• Always image the chest for thymoma — even in seronegative MG.
• MuSK MG presents with more bulbar and respiratory involvement, less ocular; treatment of choice is rituximab.
• Avoid: aminoglycosides, fluoroquinolones, macrolides, magnesium-based laxatives/antacids — can precipitate crisis.
• Pyridostigmine overdose mimics MG crisis (cholinergic crisis) — distinguish by edrophonium response or by SLUDGE symptoms (Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis).
• Pregnancy can worsen MG in the first trimester and postpartum; magnesium for preeclampsia is CONTRAINDICATED (precipitates crisis) — use levetiracetam (or valproic acid); phenytoin can also worsen weakness and is reserved for refractory seizures.

References

• MGFA 2020 — International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update (Narayanaswami et al., Neurology 2021)
• MGTX Trial — Randomized Trial of Thymectomy in Myasthenia Gravis (Wolfe et al., NEJM 2016)
• AAN — Evidence-based Guideline: Treatment of Myasthenic Crisis (Wendell & Levine, Neurohospitalist 2011)