Myasthenia gravis
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Myasthenia Gravis (MG)
Definition and Overview
Myasthenia gravis is an acquired autoimmune disorder of the neuromuscular junction (NMJ) characterized by fatigable weakness of voluntary skeletal muscles - weakness that worsens with activity and improves with rest. It is the most common NMJ disorder, with a prevalence of 43-84 per million persons and an annual incidence of approximately 1 per 300,000.
- Bradley and Daroff's Neurology in Clinical Practice
- Adams and Victor's Principles of Neurology, 12th Ed.
Pathophysiology
The core defect is a reduction in functional nicotinic acetylcholine receptors (nAChRs) at the postsynaptic membrane of the NMJ. Autoantibodies attack the receptor in several ways:
- Complement activation - IgG antibodies bind the receptor, activate complement, and cause lysis of the postsynaptic (junctional fold) membrane
- Cross-linking and accelerated degradation - Antibodies cross-link AChRs, increasing receptor internalization and proteolysis
- Blocking - Some antibodies directly block the ACh-binding site
The main immunogenic region (MIR) is located on the α-subunit of the heteropentameric AChR. With fewer functional receptors, the endplate potential falls below the threshold for triggering a muscle action potential - especially after repeated stimulation when ACh stores are partially depleted, producing the characteristic fatigue.
The thymus plays a central role: it contains myoid cells that express AChR, and thymic hyperplasia or thymoma appears to initiate or perpetuate the autoimmune response. Autoreactive T cells (overrepresentation of Vβ5.1+ TCR T cells in hyperplastic thymuses) drive the B-cell response that produces AChR antibodies.
- Medical Physiology (Boron & Boulpaep)
- Bradley and Daroff's Neurology (Autoimmune MG chapter)
Antibody Subtypes
| Antibody | Frequency | Notes |
|---|---|---|
| Anti-AChR | 80-90% of generalized MG; 50% of ocular MG | Most common; associated with thymoma when positive |
| Anti-MuSK (muscle-specific tyrosine kinase) | ~5-8% (seronegative for AChR) | More prominent facial/bulbar weakness; more severe disease |
| Anti-LRP4 (LDL receptor-related protein 4) | 1-3% | Mild-to-moderate symptoms |
| Anti-titin, anti-ryanodine receptor | In thymoma-associated MG | Markers of thymoma MG |
Thymoma-associated MG almost invariably has AChR antibodies, but not anti-MuSK or LRP4.
- Bradley and Daroff's Neurology in Clinical Practice
Epidemiology
- Prevalence: 25-125 per million (some estimates up to 200/million as diagnosis improves)
- Bimodal age distribution:
- Young peak (20-40 years): Predominantly women, associated with thymic hyperplasia, HLA-B8/DRw3
- Older peak (60s-70s): More equal sex distribution; men more often; associated with thymoma
- ~75% of patients have thymic abnormalities (85% of these are thymic hyperplasia; 10-15% are thymoma)
- Strong association with other autoimmune diseases: SLE, RA, pernicious anemia, thyroid disease
Clinical Features
Hallmark: Fatigable Weakness
Weakness that worsens with repetitive use and recovers with rest. Symptoms are typically worse at end of day or after exertion.
Ocular Features (initial in ~60% of patients)
- Ptosis (unilateral or bilateral, often asymmetric)
- Diplopia from extraocular muscle weakness
- ~15-20% of patients remain purely ocular (ocular MG); the rest generalize
Bulbar Features
- Dysphagia - dysfunction at oral, pharyngeal, and/or esophageal levels; silent aspiration in ≥35%
- Dysarthria - nasal, fatigued speech
- Dyspnea with eating, jaw fatigue
- Bulbar involvement from the outset in 6-30% of patients; dysphagia can precipitate myasthenic crisis (was the precipitant in 56% in one study)
Limb and Neck Weakness
- Proximal > distal pattern
- Neck flexor weakness (head drop)
- Respiratory muscle involvement in severe/generalized disease
Preserved Features
- Tendon reflexes are NORMAL
- Sensation is normal (pure motor disorder)
- No autonomic dysfunction (unlike Lambert-Eaton syndrome)
Myasthenic Crisis
A life-threatening exacerbation where respiratory muscles fail, requiring mechanical ventilation. Precipitants include:
- Infections (most common)
- Surgery/anesthesia
- Certain drugs (aminoglycosides, fluoroquinolones, beta-blockers, magnesium, neuromuscular blockers)
- Aspiration/dysphagia
- Tapering of immunosuppression
- Emotional stress, heat
The greatest risk of crisis is in the first year after disease onset. Overall mortality was formerly >30%; now <5% with modern ICU care.
Diagnosis
Serology
- Anti-AChR antibodies (binding, blocking, modulating) - diagnostic when positive; high specificity
- Anti-MuSK antibodies - check when AChR-negative
- Anti-LRP4 - third-line seronegative workup
Edrophonium (Tensilon) Test
Edrophonium is a short-acting acetylcholinesterase inhibitor. An IV dose produces rapid, transient improvement in ptosis or limb weakness within seconds to minutes. Sensitivity ~80-90% in generalized MG; less reliable in purely ocular MG. Now rarely performed due to cardiac risks (bradycardia, syncope) and availability of serologic tests.
Ice Pack Test
Placing an ice pack on a ptotic eyelid for 2 minutes - improvement in ptosis is a positive result. Useful, safe adjunct when edrophonium is unavailable or contraindicated.
Electrophysiology
- Repetitive nerve stimulation (RNS): A decrement of >10% in compound muscle action potential (CMAP) amplitude at 3 Hz stimulation is characteristic. Sensitivity ~50-70% in generalized MG.
- Single-fiber EMG (SFEMG): Most sensitive test (~95%); demonstrates increased "jitter" (variability in neuromuscular transmission timing) and blocking. Can be positive even when seronegative.
Imaging
- CT chest: Mandatory in all patients to detect thymoma or thymic hyperplasia. MRI is more sensitive for small thymomas.
Additional workup
- Thyroid function tests (associated thyroid disease)
- Brain/orbital MRI if diagnosis uncertain (to exclude compressive cranial nerve lesions)
Treatment
1. Symptomatic: Acetylcholinesterase Inhibitors
- Pyridostigmine (Mestinon) - First-line symptomatic agent; standard dose 30-60 mg orally every 4-6 hours
- Neostigmine - Alternative, especially IV/IM postoperatively
- These inhibit AChE, prolonging ACh in the synaptic cleft to compensate for reduced receptors
- Risk of cholinergic crisis with overdose: muscarinic effects (diarrhea, sweating, bradycardia, miosis, excessive secretions) and nicotinic effects (muscle fasciculations, then weakness). Must be distinguished from myasthenic crisis.
2. Immunosuppression
| Agent | Details |
|---|---|
| Corticosteroids (prednisone) | First-line immunosuppressive; start low (to avoid initial worsening), escalate. Alternate-day dosing reduces side effects |
| Azathioprine | Most common steroid-sparing agent; onset 6-12 months; check TPMT before use |
| Mycophenolate mofetil | Alternative to azathioprine; better tolerability |
| Methotrexate | Used in refractory cases |
| Cyclosporine | Second-line; renal toxicity limits use |
| Tacrolimus | Used in MuSK-positive MG and refractory cases |
3. Rapid/Short-term Immunotherapy
Used in crisis, pre-thymectomy optimization, or acute exacerbations:
- Plasma exchange (plasmapheresis): Removes circulating AChR antibodies; effect within 1-2 weeks, lasting several weeks. Standard series is 5-6 exchanges. AChE inhibitor doses need adjustment afterward.
- IVIG: 2 g/kg over 3-5 days; comparable efficacy to plasma exchange; easier to administer. Both offer only short-term benefit.
4. Thymectomy
- Recommended for patients aged 15-65 years with generalized MG
- Associated with ~35% remission rate and ~50% further improvement
- Effects not apparent for months; maximal benefit at ~3 years
- Best outcomes if performed within the first 1-2 years of disease
- A landmark randomized trial (Wolfe et al.) confirmed benefit of thymectomy + prednisone vs. prednisone alone over 3 years
- Not recommended for purely ocular MG stable >1 year, or prepubertal patients (thymus important for immune development)
- In thymoma: surgical removal indicated regardless of age
5. Novel Biologics (emerging therapies)
Recent systematic reviews (2024-2025) highlight:
- Efgartigimod (FcRn inhibitor - reduces IgG including AChR antibodies) - FDA approved
- Ravulizumab / Eculizumab (complement C5 inhibitors) - approved for AChR-positive generalized MG
- Rozanolixizumab (anti-FcRn)
- Rituximab (anti-CD20, B-cell depletion) - particularly effective for MuSK-positive MG; a 2025 Cochrane review assessed its evidence base [PMID: 40607605]
A 2025 network meta-analysis found novel biologics show superior efficacy compared to conventional agents in generalized MG [PMID: 40346603].
MG Subtypes Summary
| Subtype | Features |
|---|---|
| Ocular MG | Ptosis/diplopia only; ≤15-20% of patients; lower antibody positivity |
| Generalized MG | Bulbar, limb, respiratory muscle involvement |
| Thymoma-associated MG | AChR+; anti-titin/anti-RyR antibodies; often more severe |
| MuSK-positive MG | Prominent facial/bulbar/respiratory; responds poorly to AChE inhibitors; responds well to rituximab |
| Seronegative MG | Negative AChR, MuSK, LRP4; SFEMG often positive |
| Juvenile MG | Children; more favorable long-term prognosis; ~30-40% remit |
| Neonatal MG | Transient, from transplacental transfer of maternal AChR antibodies; resolves in weeks |
Differential Diagnosis
| Condition | Distinguishing Features |
|---|---|
| Lambert-Eaton syndrome | Presynaptic; improves with activity (post-tetanic potentiation); autonomic dysfunction; VGCC antibodies; often paraneoplastic (SCLC) |
| Botulism | Descending paralysis; fixed dilated pupils; presynaptic ACh release blockade |
| Miller-Fisher syndrome | Ophthalmoplegia + ataxia + areflexia; anti-GQ1b antibodies |
| Progressive external ophthalmoplegia | No fatigue; mitochondrial or genetic; no response to neostigmine |
| Graves ophthalmopathy | Exophthalmos; CT shows EOM enlargement; no ptosis |
| Motor neuron disease | Fasciculations, wasting, UMN signs |
Key Points to Remember
- MG = postsynaptic NMJ disorder (vs. Lambert-Eaton = presynaptic)
- Fatigable weakness + improvement with rest + AChE inhibitor response = classic triad
- Always screen with chest CT for thymoma
- Crisis management: intubation + mechanical ventilation if needed, IVIG or plasmapheresis, hold/adjust AChE inhibitors
- Drug-induced worsening: aminoglycosides, fluoroquinolones, beta-blockers, magnesium sulfate, D-penicillamine - avoid in MG
- Mortality has fallen from >30% to <5% with modern management
Sources:
- Bradley and Daroff's Neurology in Clinical Practice (Autoimmune MG chapter; paraneoplastic chapter)
- Adams and Victor's Principles of Neurology, 12th Ed.
- Medical Physiology (Boron & Boulpaep)
- Recent evidence: Rituximab for MG - Cochrane 2025 [PMID: 40607605]; Novel biologics network meta-analysis 2025 [PMID: 40346603]
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