Myasthenia Gravis

An autoimmune disorder with antibodies to the postsynaptic acetylcholine receptor (AchR) or (less commonly) muscle-specific tyrosine kinase (MuSK). Presents most often in females aged 10–30 and males aged 50–70.

Diagnosis

Confirmed by demonstrating muscle fatigability, typically in the ocular, facial, bulbar or limb muscles. Ptosis may improve with ice applied to the eyelid. Myasthenia gravis does not cause sensory loss, sphincter disturbance or loss of reflexes — if present, consider an alternative diagnosis and refer for expert advice.

Many patients with ocular-only symptoms are at risk of progressing to generalised disease within 2 years (more likely with positive anti-AchR antibodies). Corticosteroids may reduce this progression risk, or may simply mask emerging generalised symptoms — weigh the potential benefit against immunosuppression harms.

Investigations

• AchR antibodies — positive in ~85%. If negative, test MuSK antibodies, especially with bulbar symptoms.
• Neurophysiology — decremental response on repetitive stimulation, or positive single-fibre EMG.
• TFTs and B12 in all patients (increased risk of other autoimmune disease).
• CT chest in all patients, to check for a thymoma.
• MRI brain if ocular signs only with negative serology (exclude a structural cause).
• If investigations are equivocal/negative but suspicion remains: refer for expert consideration of an edrophonium (Tensilon) test, performed under expert care with resuscitation facilities available.

Drugs that can worsen myasthenia gravis

• Avoid: D-penicillamine, botulinum toxin type A, interferon alfa.
• Use with caution:
  • Neuromuscular blocking drugs — IV lidocaine/large-dose local anaesthetics can potentiate them (local anaesthesia itself is generally safe). Non-depolarising agents: avoid if possible (highly variable potentiation), avoid long-acting agents (e.g. pancuronium), reduce dose, monitor closely, consider a test dose. Depolarising agents: avoid if possible (variable response — receptor loss may confer resistance; cholinesterase inhibitors/vancomycin can potentiate suxamethonium).
  • Halogenated inhalational anaesthetics — increased sensitivity to the relaxant effect; monitor neuromuscular function.
  • Aminoglycosides, fluoroquinolones, macrolides, quinine — use an alternative where possible.
  • Iodinated contrast media — use non-contrast imaging where possible.

Treatment

Do not start treatment until the diagnosis is confirmed, except in an emergency. Management depends on disability degree and muscles involved — always assess breathing and swallowing. Isolated ocular symptoms or mild–moderate limb/bulbar weakness can be managed as an outpatient; more significant symptoms need inpatient management.

First-line for MuSK-negative mild generalised or ocular myasthenia: pyridostigmine (an acetylcholinesterase inhibitor — less effective, more side-prone in MuSK-positive disease). Start lower in smaller patients:

• Pyridostigmine 30mg PO TDS, increasing every 4–7 days according to response/tolerability (max 120mg 2–6×/day). Review after 4–6 weeks.
• Time doses for peak fatigue (e.g. 30–45 min before meals with bulbar weakness). Use the lowest effective dose. Muscarinic side effects (diarrhoea, cramping, glaucoma exacerbation) may respond to adding propantheline.
• Doses >540mg/day: caution — risk of receptor-downregulation tolerance, more side effects, and a cholinergic crisis being mistaken for disease worsening.
• Sustained-release pyridostigmine 180mg nocte is useful overnight only (not during the day — variable/delayed release); can substitute for the final immediate-release dose.

Immunosuppression — needed for moderate–severe disease, or an incomplete response to an adequate pyridostigmine trial. Once in remission on immunosuppression, pyridostigmine is usually no longer needed (its withdrawal, over a few weeks, avoids mistaking its side effects — twitching, cramping — for disease activity).

• High-dose corticosteroids can transiently worsen symptoms in the first 3–7 days (start as an inpatient, or work up slowly as an outpatient); use lower doses in ocular myasthenia; start a steroid-sparing agent concurrently.
  • Prednisolone 5mg PO daily (morning), increase by 5mg every 3 days to max 1mg/kg (up to 75mg) daily; after 4–6 weeks reduce by 5mg every 2 weeks to 25mg daily, then taper further per response.
  • Plus azathioprine 1.5–2.5mg/kg PO daily, OR mycophenolate mofetil 500mg PO BD (max 1500mg BD), OR mycophenolate sodium 360mg PO BD (max 1080mg BD).
  • Methotrexate is an alternative steroid-sparing drug.