Decision support only — not a substitute for neurology, the international consensus guidance, or eTG. Myasthenia is a treatable antibody-mediated disorder of the neuromuscular junction; the practical stakes are recognising a crisis before the numbers fall (trend the FVC, not the oximeter), matching therapy to the antibody, and not missing the two dangerous look-alikes — checkpoint-inhibitor MG (which travels with myocarditis) and LEMS (which travels with small-cell lung cancer). Verify all doses and local access.
1 The neuromuscular junction & what the antibodies do
Normal transmission
- SequenceNerve action potential → voltage-gated Ca²⁺ channels open → acetylcholine released → binds postsynaptic AChR → endplate depolarises → muscle fibre fires.
- Safety factorNormally more ACh and more receptors than needed. MG erodes that reserve, so transmission fails with repeated use → fatigable weakness.
- Clean-upAcetylcholinesterase breaks ACh down in the cleft — the target of pyridostigmine.
What the antibodies do
- AChR~85% of generalised MG. Block, cross-link and complement-mediated destruction of the postsynaptic folds → fewer receptors. (Complement is why C5 inhibitors work.)
- MuSK~5–8%. IgG4, disrupts AChR clustering; complement-independent → C5 inhibitors don't help, but FcRn blockers and rituximab do.
- LRP4 / seronegativeSmall groups; ~10% have no detectable antibody but the same disease.
- PyridostigmineBlocks acetylcholinesterase → more ACh in the cleft → props up transmission. Symptomatic only, not disease-modifying.
2 Recognise & classify
The hallmark
- FatigableWeakness worsens with use and through the day, recovers with rest.
- OcularFatigable ptosis and diplopia, pupil spared; Cogan lid twitch.
- Bulbar/limbDysarthria, dysphagia, chewing fatigue, neck and proximal limb weakness, dyspnoea.
Two clinical types
- Ocular~15% stay ocular; ~50% generalise within ~2 years (most within 2–3), especially if AChR+.
- GeneralisedOcular + bulbar/limb/respiratory. Graded by the MGFA classification (I ocular → V intubation).
MuSK is different
- PhenotypeProminent bulbar, facial, neck and respiratory weakness, tongue wasting; crisis-prone.
- DrugOften intolerant of / worsened by pyridostigmine — cholinergic hypersensitivity.
3 Confirm the diagnosis
Antibodies
- AChRPositive in ~85% generalised, ~50% ocular — high specificity.
- MuSK~5–8%, almost always AChR-negative — send if AChR negative.
- ThenLRP4; ~10% seronegative. Anti-striational antibodies hint at thymoma.
Electrophysiology
- RNSRepetitive nerve stimulation → >10% decrement at low frequency.
- SFEMGSingle-fibre EMG → increased jitter; most sensitive, but not specific.
Bedside & imaging
- Ice packPtosis improves after cooling — quick, useful for ocular MG.
- ThymusCT/MRI chest in everyone — thymoma in ~10–15%, hyperplasia commoner.
- AlsoThyroid function and screen for associated autoimmune disease.
4 Treatment — the backbone
Symptomatic
- PyridostigmineFirst-line symptom relief; titrate to effect. Cholinergic effects: cramps, diarrhoea, secretions, bradycardia.
- LimitControls symptoms, doesn't touch the autoimmune process — most generalised MG also needs immunotherapy.
Immunosuppression
- SteroidsPrednisolone is the workhorse. A high starting dose can transiently worsen MG in the first 1–2 weeks (the "steroid dip") — build up, or cover with IVIG/PLEX if bulbar/severe.
- SparingAdd early to spare steroid: azathioprine (usual first choice), mycophenolate, others.
Rescue / bridge
- IVIG or PLEXFor crisis, severe exacerbation, or before thymectomy. PLEX tends to act faster.
- Choose byContraindications — avoid PLEX in sepsis; caution with IVIG in renal failure, hypercoagulability, IgA deficiency.
5 Thymectomy & rituximab
Thymectomy
- ThymomaResect in everyone with a thymoma, whenever feasible (oncological indication).
- AChR+ generalisedNon-thymomatous → thymectomy improves outcomes: less prednisone, better scores, fewer admissions MGTX. Best evidence roughly age 18–50/<65, early.
- Not forMuSK, LRP4 or agrin MG — no benefit. Seronegative generalised: consider only if failing/intolerant of immunosuppression.
Rituximab (anti-CD20)
- MuSKResponds well — reach for rituximab early in refractory MuSK MG (B-cell/IgG4-driven).
- AChRMixed: BeatMG was negative, but RINOMAX suggested benefit in new-onset generalised disease. An option in refractory AChR MG.
6 New targeted biologics — for refractory disease & to spare steroids
Two mechanism classes now have phase 3 evidence and approvals. They act fast and reduce steroid exposure, but they're expensive and access varies — confirm PBS status before promising them.
| Class | Agents | Works for | Notes |
|---|
| Complement C5 inhibitors |
Eculizumab REGAIN, ravulizumab CHAMPION (q8-weekly), zilucoplan RAISE (SC daily) |
AChR+ only (complement-mediated disease) |
Rapid; steroid-sparing. Meningococcal vaccination + prophylaxis — Neisseria risk with C5 blockade. |
| FcRn inhibitors |
Efgartigimod ADAPT, rozanolixizumab MycarinG, nipocalimab |
AChR+ — and rozanolixizumab/nipocalimab also approved for MuSK+ |
Lower total IgG (including the pathogenic antibody); onset ~1 week; cyclical dosing; headache with rozanolixizumab. |
The antibody type steers the choice: complement inhibitors for AChR+ disease, FcRn blockers across AChR+ and MuSK+. Both are aimed at the refractory patient and at getting people off long-term steroids.
7 Myasthenic crisis
Recognise it early
- DefinitionRespiratory failure or severe bulbar weakness needing ventilatory support/airway protection.
- MonitorSerial FVC and NIF (2–3×/day) — falling FVC (<15–20 mL/kg or <1 L) or rapid decline → escalate.
- TrapDon't trust SpO₂ or ABG — they fall late. Hypercapnia is a pre-terminal sign, not an early one.
Triggers & drugs to avoid
- TriggersInfection (commonest), surgery, aspiration, pregnancy, and tapering immunosuppression.
- DrugsAminoglycosides, fluoroquinolones, macrolides, telithromycin, beta-blockers, IV magnesium, procainamide, quinine, neuromuscular blockers, checkpoint inhibitors, penicillamine.
Manage
- SupportICU; early NIV/HFNC before exhaustion — but a poor cough or heavy secretions from bulbar weakness means intubate rather than persist.
- TreatIVIG or PLEX; find and fix the trigger.
- HoldPause pyridostigmine if intubated (reduces secretions); avoid the precipitant drugs.
8 Checkpoint-inhibitor MG & the neuro complications of ICIs
ICI-related MG — treat it as dangerous
- PatternOften de novo, early (first 1–2 cycles), severe and fast-moving; AChR+ or seronegative.
- The triadMG + myositis + myocarditis overlap — high mortality. In any checkpoint patient with new ptosis, diplopia or weakness, check CK, troponin and ECG.
- ManageHold the ICI, high-dose steroids, early IVIG/PLEX, cardiology if troponin/ECG abnormal; pyridostigmine cautiously.
The wider ICI neuro spectrum
- RangeNeuro immune-related events in up to ~1 in 10: MG, myositis, Guillain-Barré-like neuropathy, encephalitis, aseptic meningitis, hypophysitis.
- PrincipleTreatment of neuromuscular irAEs differs from the classic diseases — steroids and immunomodulation, with oncology and neurology together.
9 Lambert-Eaton myasthenic syndrome — the mirror image
What it is
- MechanismPresynaptic: P/Q-type voltage-gated calcium channel antibodies → reduced ACh release.
- Cancer~50% paraneoplastic — small-cell lung cancer. Screen (CT chest, PET) and repeat surveillance if negative.
- ClinicalProximal leg weakness, autonomic features (dry mouth), hyporeflexia; ocular/bulbar less prominent than MG.
How it differs from MG
- FacilitationPower and reflexes briefly improve after exercise — the opposite of MG's fatigability.
- RNSLow resting CMAP with an increment after high-frequency stimulation or brief exercise — mirror image of the MG decrement.
- TreatAmifampridine (3,4-DAP) first-line (more ACh release); treat the SCLC; immunotherapy (steroids/sparing, IVIG/PLEX) for severe disease.
Guidelines & reviews. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update (Narayanaswami et al, Neurology 2021; original Sanders et al 2016) — symptomatic and immunosuppressive treatment, IVIG/PLEX, crisis, thymectomy, MuSK MG, pregnancy; MGFA clinical classification; Gilhus, "Myasthenia Gravis," NEJM 2016; eTG; PBS.
Trials. MGTX (thymectomy + prednisone vs prednisone in AChR+ non-thymomatous generalised MG, NEJM 2016); REGAIN (eculizumab, Lancet Neurol 2017); CHAMPION-MG (ravulizumab); RAISE (zilucoplan); ADAPT (efgartigimod, Lancet Neurol 2021); MycarinG (rozanolixizumab); RINOMAX (rituximab in new-onset generalised MG, JAMA Neurol 2022); BeatMG (rituximab in AChR MG — negative).
Caveats. Match therapy to the antibody: complement inhibitors work only in AChR+ disease; FcRn blockers and rituximab cover MuSK. Thymectomy helps AChR+ non-thymomatous generalised MG, not MuSK/LRP4. In crisis, trend the FVC/NIF — oximetry and ABG reassure falsely until late. Checkpoint-inhibitor MG can co-occur with myocarditis (check troponin), and new LEMS mandates a small-cell lung cancer hunt. Confirm PBS status for the biologics. Verify all doses. Companion to the neuromuscular set (myopathy, MND) and the ILD/checkpoint-toxicity material.