Myasthenia Gravis (MG)

Definition and Overview

• Bradley and Daroff's Neurology in Clinical Practice
• Adams and Victor's Principles of Neurology, 12th Ed.

Pathophysiology

1. Complement activation - IgG antibodies bind the receptor, activate complement, and cause lysis of the postsynaptic (junctional fold) membrane
2. Cross-linking and accelerated degradation - Antibodies cross-link AChRs, increasing receptor internalization and proteolysis
3. Blocking - Some antibodies directly block the ACh-binding site

• Medical Physiology (Boron & Boulpaep)
• Bradley and Daroff's Neurology (Autoimmune MG chapter)

Antibody Subtypes

• 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

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

• Infections (most common)
• Surgery/anesthesia
• Certain drugs (aminoglycosides, fluoroquinolones, beta-blockers, magnesium, neuromuscular blockers)
• Aspiration/dysphagia
• Tapering of immunosuppression
• Emotional stress, heat

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

Ice Pack Test

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

3. Rapid/Short-term Immunotherapy

• 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)

• 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]

MG Subtypes Summary

Differential Diagnosis

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

• 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]

Painkiller for Injection Site Pain After Dog Bite (Rabies PEP)

Recommended Painkiller

Note on NSAIDs: Some experts prefer avoiding NSAIDs like ibuprofen around the time of vaccination, as there is theoretical concern that reducing inflammation may slightly blunt the immune response. Paracetamol is generally preferred.

Also helpful for local pain:

• Apply a cold/ice pack (wrapped in cloth) on the injection site for 10-15 minutes to reduce swelling and pain
• Do NOT massage the injection site

Important reminders

• Do NOT stop or delay the rabies vaccine series due to injection pain - completing all doses on schedule is critical
• Do NOT take aspirin (especially in children - risk of Reye's syndrome)
• If pain is severe, the injection site becomes hot, red, and increasingly swollen after 48 hours, or you develop fever above 38.5°C - see your doctor, as this may indicate a local infection
• Antihistamines (e.g., cetirizine 10 mg once daily) can help if there is significant itching at the site

⚕️ Important: This is general guidance. Always follow the advice of the doctor who administered your PEP, as they know your full medical history and can recommend the most appropriate option for you.