Key Facts

MG is the commonest disorder of the neuromuscular junction. Diagnosis requires demonstration of fatigable weakness and serological/electrophysiological confirmation. Thymoma must be excluded in all patients.

Epidemiology

Prevalence ~15-20 per 100,000. Bimodal: young women (20-30s, associated with thymic hyperplasia) and older men (60-70s, associated with thymoma). Prevalence rising (improved diagnosis, aging population).

Aetiology

• Anti-AChR antibodies (~85%): IgG1/3 targeting the nicotinic acetylcholine receptor at the postsynaptic NMJ → complement-mediated damage, receptor cross-linking/internalisation, and functional block
• Anti-MuSK antibodies (~5-10%): IgG4 targeting muscle-specific kinase; different clinical phenotype (bulbar predominant, facial/respiratory weakness, muscle atrophy)
• Seronegative (~5-10%): some have low-affinity AChR or anti-LRP4 antibodies
• Thymic pathology: thymoma (10-15%), thymic hyperplasia (65%); thymus contains AChR-like epitopes that may initiate autoimmunity

Pathophysiology

Anti-AChR antibodies bind postsynaptic AChR → complement activation → destruction of postsynaptic membrane folds → reduced AChR density → impaired neuromuscular transmission → fatigable weakness. The safety factor of neuromuscular transmission is reduced such that repeated stimulation leads to progressive transmission failure.

Ocular MG

• Ptosis (often asymmetric, may be alternating): worsens with sustained upgaze (Cogan lid twitch — overshoot on returning from downgaze)
• Diplopia: from extraocular muscle weakness (any pattern — mimics any cranial nerve palsy)
• Pupils NEVER affected (distinguishes from CN III palsy)

Generalised MG

• Bulbar: dysarthria, dysphagia, nasal speech, facial weakness (myasthenic snarl)
• Limb weakness: proximal > distal; arms > legs initially
• Respiratory: dyspnoea, orthopnoea → myasthenic crisis
• Neck flexion weakness (dropped head)

Myasthenic Crisis

• Respiratory failure requiring ventilatory support
• Triggered by infection, surgery, medication changes, stress
• Medical emergency — ITU admission

Red Flags

• Rapid respiratory deterioration
• FVC <20 mL/kg or declining
• Severe bulbar weakness (aspiration risk)
• New diagnosis with thymoma on CT

Serology

• Anti-AChR antibodies: positive in ~85% of generalised MG, ~50% of ocular MG; highly specific
• Anti-MuSK antibodies: if AChR negative; ~40% of AChR-seronegative patients
• Anti-LRP4 antibodies: research use; some seronegative patients

Neurophysiology

• Repetitive nerve stimulation (RNS): >10% decremental response at 3 Hz — diagnostic
• Single-fibre EMG (SFEMG): increased jitter; most sensitive test (~95% sensitivity); specialist investigation

Imaging

• CT thorax: MANDATORY in all MG patients to exclude thymoma
• MRI thorax: if CT equivocal

Bedside

• Ice pack test: place ice on closed eyelid for 2 minutes → improvement in ptosis supports MG (cooling improves NMJ transmission)
• FVC: serial monitoring in acute settings (myasthenic crisis)

Other

• TFTs: associated autoimmune thyroid disease
• ANA, anti-dsDNA: associated autoimmunity
• Edrophonium (Tensilon) test: largely abandoned in UK (cardiac risk); replaced by ice pack test

Symptomatic

• Pyridostigmine 30-120 mg QDS (anticholinesterase; first-line; side effects: cholinergic — abdominal cramps, diarrhoea, increased secretions, bradycardia)

Immunosuppression

• Prednisolone: start low (5-10 mg OD) and increase slowly (can initially worsen MG — "steroid dip"); maintenance 5-20 mg OD
• Azathioprine 2-3 mg/kg/day: steroid-sparing; check TPMT before starting; takes 3-6 months for effect
• Mycophenolate mofetil 1-3 g/day: if azathioprine not tolerated
• Rituximab: especially effective in MuSK-MG; increasingly used in refractory AChR-MG
• Eculizumab (anti-C5 complement; REGAIN trial; NICE TA992): for refractory generalised AChR-positive MG

Myasthenic Crisis

• IV immunoglobulin 0.4 g/kg/day × 5 days OR plasma exchange (5 exchanges over 10-14 days)
• ITU: monitor FVC closely; intubate if FVC <15-20 mL/kg or rapidly declining
• Identify and treat trigger (infection commonest)

Thymectomy

• Indicated if: thymoma (any age — curative intent) OR non-thymomatous generalised AChR+ MG in patients aged 18-65 (MGTX trial showed benefit)
• Not typically performed in MuSK-MG or seronegative MG

Drugs to AVOID

• Aminoglycosides, macrolides, fluoroquinolones, beta-blockers, D-penicillamine, phenytoin, quinine, magnesium sulphate

Referral Criteria

• All suspected MG: neurology (specialist neuromuscular centre)
• Thymoma: thoracic surgery
• Crisis: ITU

With modern immunotherapy, MG mortality is <5%. Ocular MG: ~50% generalise within 2 years; if remains ocular for 2 years, low risk of generalisation. Thymoma-associated MG: outcomes depend on tumour staging. Remission rates: ~10-20% achieve complete stable remission. Anti-MuSK MG: often more difficult to treat but responds well to rituximab. Most patients have a good quality of life with appropriate treatment.

Myasthenia Gravis Foundation of America (MGFA) Classification

MG vs Lambert-Eaton Syndrome