Myasthenia gravis
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Myasthenia Gravis (MG)
Definition
Acquired myasthenia gravis is the most common primary disorder of neuromuscular transmission (NMT). Autoantibodies bind to proteins at the neuromuscular junction (NMJ) - most commonly the acetylcholine receptor (AChR) - disrupting normal neuromuscular transmission and producing characteristic fatigable muscle weakness.
- Bradley and Daroff's Neurology in Clinical Practice
- Goldman-Cecil Medicine
Pathophysiology
The NMJ has no blood-nerve barrier, making it uniquely vulnerable to autoimmune attack by circulating factors.
Three main antibody targets:
| Antibody | % of MG | Mechanism |
|---|---|---|
| Anti-AChR (IgG1/IgG3) | ~85% of generalized MG | Complement activation → destruction of post-junctional membrane; cross-linking + internalization of AChRs; direct blockade of ACh binding |
| Anti-MuSK (IgG4) | Up to 50% of AChR-negative GMG | Inhibits signaling that concentrates AChRs on the postsynaptic surface |
| Anti-LRP4 | Small subset | Interferes with agrin-MuSK signaling, disrupting NMJ integrity |
Other putative targets include agrin and cortactin.
The diagram below shows antibody-mediated AChR cross-linking and removal:
Role of the thymus:
-
In early-onset MG, thymic hyperplasia with germinal centers suggests immune tolerance breakdown initiated in the thymus
-
In thymoma-associated MG, deficiency of the AIRE protein leads to reduced regulatory T cells and increased autoreactivity
-
Thymoma is found in ~10-15% of MG patients
-
Goldman-Cecil Medicine, p. 4111
Epidemiology
-
US prevalence: ~20/100,000 (~60,000 patients total)
-
Prevalence has increased over 50 years due to better ascertainment, reduced mortality, and an aging population
-
Before age 40: women affected ~3x more often than men
-
After age 50: incidence is higher in males; majority of US MG patients are now over 50
-
Genetic predisposition: ~5% of patients have an affected family member; heritability index ~0.65
-
Bradley and Daroff's Neurology, p. 2770
Clinical Subtypes
| Subtype | Key Features |
|---|---|
| Ocular MG (OMG) | Weakness confined to extraocular muscles; 10-15% of Caucasians, up to 58% in Asians; if no generalization by 2 years, 90% chance it stays ocular |
| Generalized MG - Early onset (EOMG) | Age <50, predominantly female, AChR-ab+, thymic hyperplasia, HLA-A1/B8/DRw3 |
| Generalized MG - Late onset (LOMG) | Age >50, predominantly male, may have anti-titin and anti-ryanodine receptor antibodies, atrophic thymus |
| Thymomatous MG | Equal sex ratio, peaks at age 50, striated muscle antibodies common |
| MuSK MG | Predominantly female, cranial/bulbar predominance with muscle atrophy, proximal limb and respiratory involvement; often ChEI-resistant |
| Seronegative MG | No detectable autoantibodies by standard testing |
Clinical Presentation
Weakness that worsens with activity and improves with rest is the hallmark.
Initial symptoms:
- Ptosis or diplopia: ~two-thirds of patients (nearly all develop both within 2 years)
- Difficulty chewing, swallowing, or speaking: ~one-sixth
- Limb weakness: ~10%
Ocular features: Ptosis, ophthalmoplegia, and diplopia from fatigable weakness of periocular muscles - asymmetric and variable.
Fig: Progressive right lid ptosis during sustained gaze (A-B), incomplete superior movement both eyes (C), skew deviation on left gaze (D), and incomplete movement on right gaze (E).
Pattern of fatigue: Symptoms are typically worst in the evening, worsen with prolonged muscle use, and may be minimal in the morning.
Bulbar involvement:
- Dysphagia occurs at oral, pharyngeal, and esophageal levels
- Silent aspiration in ≥35% of MG patients with dysphagia
- Dysarthria ("nasal voice") and difficulty chewing
- Dysphagia is a major precipitant of myasthenic crisis in ~56% of cases
Respiratory weakness can lead to myasthenic crisis - respiratory failure requiring mechanical ventilation.
Diagnosis
Serological Testing
- Anti-AChR antibodies (binding, blocking, modulating): Positive in ~85% generalized MG; establishes diagnosis when elevated
- Anti-MuSK antibodies: Test in AChR-ab-negative patients
- Anti-LRP4 antibodies: Considered in double-seronegative patients
Electrodiagnostic Testing
- Repetitive nerve stimulation (RNS): Decremental response ≥10% at low frequencies (2-3 Hz) - characteristic but not always positive, especially in OMG
- Single-fiber EMG (SFEMG): Most sensitive test; shows increased jitter and impulse blocking; required when RNS and antibodies are negative (particularly in OMG)
Pharmacological Testing
- Edrophonium (Tensilon) test: Short-acting ChEI; brief improvement in ptosis/ophthalmoplegia confirms diagnosis. Requires monitoring (risk of bradycardia/cholinergic crisis)
- Ice pack test: Application of ice to ptotic eyelid - improvement suggests MG (cold reversibly improves NMT)
Imaging
-
CT chest (with contrast): Mandatory in all MG patients to screen for thymoma
-
Wills Eye Manual; Bradley and Daroff's Neurology
Treatment
Treatment is layered based on acuity and severity.
1. Symptomatic Therapy
Pyridostigmine (Mestinon) - acetylcholinesterase inhibitor; first-line symptomatic treatment
- Prevents ACh breakdown, increasing available transmitter at the NMJ
- Dose: typically 30-60 mg PO every 4-6 hours
- Note: Often less effective or even worsening in MuSK-MG
2. Immunosuppressive Therapy
| Agent | Role |
|---|---|
| Prednisone | First-line long-term immunosuppression; initial worsening possible |
| Azathioprine | Steroid-sparing agent; onset takes 12-18 months |
| Mycophenolate mofetil | Alternative steroid-sparing agent |
| Cyclosporine / Tacrolimus | Second-line options |
| Rituximab | Particularly effective in MuSK-MG; now supported by a 2025 Cochrane systematic review |
| Methotrexate | Alternative in refractory cases |
3. Rapid Short-Term Therapies (for crisis or pre-operatively)
- Plasmapheresis (PLEX): Rapidly removes circulating antibodies; effect lasts 4-6 weeks
- Intravenous immunoglobulin (IVIg): Comparable efficacy to PLEX; mechanism includes Fc receptor saturation and immune modulation
4. Novel Biologics (FDA-Approved)
Recent years have seen approval of targeted therapies that dramatically expand options for generalized refractory MG:
Complement Inhibitors (C5 blockade):
- Eculizumab (anti-C5 monoclonal Ab, IV q2 weeks) - AChR-ab+ GMG
- Ravulizumab (long-acting anti-C5, IV q8 weeks) - AChR-ab+ GMG
- Zilucoplan (synthetic peptide targeting C5, SC daily) - AChR-ab+ GMG
- All require meningococcal vaccination
FcRn Inhibitors (reduce IgG antibody levels):
- Efgartigimod (IV or SC, weekly x4 cycles) - generalized MG
- Rozanolixizumab - SC, approved for GMG
A 2025 network meta-analysis comparing these novel biologics confirmed meaningful superiority over placebo for multiple outcomes. A 2024 network meta-analysis also evaluated the risk-benefit profile across agents.
- Harrison's Principles of Internal Medicine 22E (2025)
5. Thymectomy
- Recommended for all thymoma patients (does not cure MG but removes tumor)
- Beneficial in non-thymomatous AChR-ab+ patients aged 18-60 (MGTX trial showed improved outcomes vs. prednisone alone at 3 years)
- Less clear benefit in late-onset, MuSK-MG, or seronegative MG
Myasthenic Crisis
A life-threatening emergency involving respiratory failure from severe diaphragmatic and accessory muscle weakness.
Precipitants: Infection, surgery, aspiration, certain medications (aminoglycosides, fluoroquinolones, magnesium, beta-blockers, neuromuscular blocking agents), or rapid tapering of immunotherapy.
Management:
- Secure airway (early intubation threshold is low)
- Hold pyridostigmine (can increase secretions)
- PLEX or IVIg as primary immune therapy
- ICU monitoring
Key Drugs to Avoid in MG
- Aminoglycoside antibiotics
- Fluoroquinolones
- Magnesium sulfate
- Beta-blockers (systemic)
- Neuromuscular blocking agents (depolarizing and non-depolarizing)
- D-penicillamine (can induce MG)
Summary Table
| Feature | Detail |
|---|---|
| Pathogenesis | Autoantibodies to AChR, MuSK, or LRP4 at NMJ |
| Hallmark symptom | Fatigable weakness, worse with activity, better with rest |
| Most common initial symptom | Ptosis/diplopia (~67%) |
| Key diagnostic test | Anti-AChR antibody; SFEMG most sensitive |
| First-line symptomatic Rx | Pyridostigmine |
| First-line immunosuppression | Prednisone ± azathioprine |
| Crisis Rx | PLEX or IVIg + ICU support |
| Emerging therapies | Complement inhibitors (eculizumab, ravulizumab, zilucoplan); FcRn inhibitors (efgartigimod, rozanolixizumab) |
Sources: Bradley and Daroff's Neurology in Clinical Practice; Goldman-Cecil Medicine; Harrison's Principles of Internal Medicine 22E (2025); Ganong's Review of Medical Physiology; Cochrane Review on Rituximab for MG (2025); Network Meta-Analysis of Novel Biologics in gMG (2025)
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