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Myasthenia Gravis (MG)

Definition and Pathophysiology

1. Complement activation - causing lysis of the muscle endplate membrane
2. Cross-linking AChRs - accelerating receptor internalization and degradation
3. Direct blockade of ACh binding sites

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Epidemiology

• US prevalence: approximately 20 per 100,000 (~60,000 patients)
• Prevalence has been increasing over the past 50 years (partly due to better diagnosis in the elderly)
• Women affected ~3x more than men before age 40; incidence roughly equal after age 50
• Mean age of onset: women 28-35 years; men 42-49 years
• The majority of MG patients in the US are now over age 50
• A thymoma is found in 10% of MG patients; one-third of thymoma patients develop MG
• Bradley and Daroff's Neurology in Clinical Practice, Chapter 108

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Clinical Features

Cardinal Feature

Ocular Symptoms (initial in ~65% of patients)

• Ptosis - often asymmetric, may shift from eye to eye (this shifting is virtually pathognomonic of MG)
• Diplopia - from weakness of extraocular muscles without pupillary involvement
• Lid overshoot after downgaze then upgaze ("lid twitch sign" or Cogan's sign)
• Ocular MG: remains confined to ocular muscles in ~10-15% (up to 58% in Asian pediatric populations)

Bulbar Symptoms (initial in ~16% of patients)

• Dysphagia - can occur at oral, pharyngeal, or esophageal levels; silent aspiration in >35% of those with dysphagia
• Dysarthria - nasal or slurred speech worsening with prolonged talking
• Jaw fatigue - worsening during chewing of tough foods; patient may hold jaw closed with hand ("jaw prop" sign)
• Facial weakness - "myasthenic snarl" instead of a smile, flat affect, mask-like facies

Neck and Limb Weakness

• Neck extensors commonly affected - "dropped head syndrome"
• Proximal > distal limb weakness
• Rarely, initial weakness in neck, finger/elbow extensors, hip flexors, or ankle dorsiflexors

Simpson Test (Fatigability Test)

Important Negative Findings

• Tendon reflexes: normal
• Sensation: normal
• Pupils: unaffected (key differentiator from other NMJ disorders and third nerve palsy)

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Disease Course

• Maximum weakness in the first year in two-thirds of patients
• Ocular symptoms usually generalize within 2 years if untreated
• Three historical stages (pre-immunosuppression era):
  • Active stage: fluctuating, worsening symptoms
  • Inactive stage: fluctuations occur but tied to identifiable triggers
  • Burnt-out stage: fixed weakness, muscle atrophy (rare today)
• Factors that worsen MG: emotional upset, infection (especially viral respiratory), thyroid dysfunction, pregnancy, menstruation, surgery, drugs affecting NMT, fever

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Diagnosis

1. Clinical Recognition

• Characteristic pattern of fatigable, fluctuating weakness in specific muscle groups (ocular, bulbar, neck, proximal limbs)

2. Serology

• Anti-AChR antibodies (binding, blocking, modulating) - most sensitive and specific initial test
• Anti-MuSK antibodies if AChR-negative
• Anti-LRP4 antibodies for double-seronegative cases
• Thymoma-associated MG: also test for anti-titin and anti-ryanodine receptor antibodies

3. Edrophonium (Tensilon) Test

• IV edrophonium (short-acting AChE inhibitor) causes transient improvement of weakness within 30-60 seconds if MG
• Also used to distinguish myasthenic crisis (weakness improves with edrophonium) from cholinergic crisis (weakness worsens with edrophonium)
• Requires atropine on standby (risk of bradycardia/bronchospasm)

4. Electrodiagnostics

• Repetitive nerve stimulation (RNS) at 2-3 Hz: decremental response (>10% decrement) in compound muscle action potential - characteristic of postsynaptic NMJ defect
• Single-fiber EMG (SFEMG): increased jitter - most sensitive test for NMJ dysfunction

5. Imaging

• CT chest (contrast-enhanced): mandatory in all newly diagnosed MG patients to evaluate for thymoma

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Classification (Osserman/MGFA)

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Treatment

1. Symptomatic Treatment

• Pyridostigmine (Mestinon) - AChE inhibitor, first-line symptomatic therapy; 60 mg every 4-6 hours. Does NOT modify disease course. Longer-acting than neostigmine (onset 60-120 min, duration 3-6 hours).

2. Rapid Immunomodulation (for crisis or acute worsening)

• Plasma exchange (PLEX/plasmapheresis) - removes circulating antibodies; fastest onset (days)
• IV Immunoglobulin (IVIG) - equivalent efficacy to PLEX; 2 g/kg over 5 days; preferred when vascular access is difficult

3. Long-term Immunosuppression

• Corticosteroids (prednisone) - mainstay; note that high-dose steroids may transiently worsen MG before improvement ("steroid dip") - typically start low and titrate up
• Azathioprine - most commonly used steroid-sparing agent; onset delayed 12-18 months
• Mycophenolate mofetil - alternative steroid-sparing agent
• Ciclosporin / Tacrolimus - for refractory cases
• Methotrexate - also used as an alternative

4. Biological Therapies (newer agents)

• Eculizumab (anti-C5 complement inhibitor) - approved for generalized AChR+ MG
• Ravulizumab - longer-acting anti-C5
• Efgartigimod (anti-FcRn) - reduces IgG antibody levels including anti-AChR
• Rozanolixizumab (anti-FcRn)
• A 2025 network meta-analysis (PMID 40346603) comparing novel biologics found significant differences in efficacy and tolerability across agents in generalized MG.

5. Thymectomy

• Indicated in all MG patients with thymoma (mandatory)
• Recommended in non-thymomatous AChR+ generalized MG patients aged 18-65 years
• The majority of generalized MG patients will undergo thymectomy, which improves long-term outcomes
• Surgical approaches include transsternal and video-assisted thoracoscopic surgery (VATS)
• Thymoma-associated MG almost invariably has AChR antibodies (not MuSK or LRP4)

6. Drugs to Avoid in MG

• Aminoglycoside antibiotics (gentamicin, tobramycin)
• Fluoroquinolones, macrolides
• Neuromuscular blocking agents (non-depolarizing > depolarizing)
• Beta-blockers
• Magnesium (blocks NMJ)
• Chloroquine / hydroxychloroquine
• D-penicillamine (can induce MG de novo)

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Myasthenic Crisis

• Definition: severe exacerbation of MG weakness requiring respiratory support (intubation/ventilation)
• Precipitants: infection (especially respiratory), aspiration, surgery, drugs, rapid steroid taper, stress
• Dysphagia is a precipitant in ~56% of crises
• Management: ICU admission, intubation if needed, PLEX or IVIG, hold/reduce pyridostigmine (excess ACh can worsen secretions), treat underlying trigger

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MG vs. Lambert-Eaton Myasthenic Syndrome (LEMS) - Key Distinction

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Special Populations

• Neonatal MG: Transient (weeks) from maternal IgG crossing placenta; ~12% of infants born to MG mothers; hypotonia, poor feeding, weak cry; self-limiting
• Congenital myasthenic syndromes: NOT autoimmune; genetic mutations in NMJ proteins; AChE inhibitors helpful for many subtypes
• Pediatric MG: Ocular form predominates, especially in Asian children (up to 58% remain ocular)

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• Bradley and Daroff's Neurology in Clinical Practice, 8th ed., Chapter 108
• Ganong's Review of Medical Physiology, 26th ed.
• Morgan and Mikhail's Clinical Anesthesiology, 7th ed.
• Tintinalli's Emergency Medicine, p. 587
• Recent evidence: PMID 40346603 - 2025 network meta-analysis on novel biologics in MG treatment