Myasthenia Gravis

Myasthenia gravis (MG) is the prototype autoimmune disorder of the neuromuscular junction (NMJ), characterised by antibody-mediated destruction of post-synaptic acetylcholine receptors (AChR). The clinical hallmark is fatigable, fluctuating skeletal muscle weakness that worsens with sustained activity and improves with rest — a fact that drives almost every exam question on this topic.

Definition & classification

MG is a post-synaptic, antibody-mediated disorder of the NMJ. Autoantibodies reduce the number of functional AChRs, so the safety factor of neuromuscular transmission falls and repetitive firing leads to progressive weakness.

Serological classification (high-yield):

Subtype	Antibody	Frequency	Key associations
Generalised AChR-positive	Anti-AChR (binding)	~85% of generalised MG	Thymic hyperplasia, thymoma
Ocular MG	Anti-AChR (lower titres)	~50% positive	Confined to extra-ocular/levator muscles
MuSK-MG	Anti-MuSK (muscle-specific kinase)	~5–8%	Bulbar/respiratory/neck weakness, facial wasting, poor response to anticholinesterases
LRP4-MG	Anti-LRP4	~1–3%	Often milder
Seronegative MG	None detectable	~6–10%	Diagnosis on electrophysiology + clinical

Osserman clinical staging (classic eponym):

• I – Ocular only
• IIa – Mild generalised
• IIb – Moderate generalised + bulbar
• III – Acute fulminating
• IV – Late severe (with crisis)

High-yield: Anti-AChR antibodies are present in ~85% of generalised MG but only ~50% of purely ocular MG. A negative antibody test does NOT exclude MG.

Etiology & pathophysiology

The triggering autoantigen is the nicotinic AChR on the post-synaptic membrane. Antibodies (mainly IgG1 and IgG3, which are complement-fixing) cause weakness by three mechanisms:

1. Complement-mediated lysis of the post-synaptic membrane → loss of junctional folds (most important).
2. Antigenic modulation – cross-linking of receptors → accelerated internalisation and degradation.
3. Functional blockade of the ACh-binding site (least important).

The net effect: reduced AChR density and simplified, flattened post-synaptic folds, lowering the safety factor of transmission. With repetitive nerve activity, the normal physiological decline in ACh release per impulse now drops the end-plate potential below threshold in more fibres → decremental response and fatigable weakness.

MuSK is essential for AChR clustering at the end-plate; anti-MuSK antibodies are predominantly IgG4 (non-complement-fixing), which explains the different phenotype and the poor/paradoxical response to anticholinesterases.

Thymus link: The thymus is abnormal in most patients — thymic hyperplasia (germinal centres) in ~65% and thymoma in ~10–15%. The thymus contains myoid cells expressing AChR, presumed to break tolerance.

High-yield: Thymoma occurs in ~10–15% of MG patients; conversely, 30–50% of patients with a thymoma develop MG. Always image the chest (CT/MRI) in newly diagnosed MG.

Clinical features

Weakness is fluctuating, fatigable, and worse towards the end of the day or after exertion, improving after rest. There is no sensory loss, normal reflexes, and no autonomic involvement (helps separate from Lambert-Eaton).

Pattern of involvement:

• Ocular (>50% present this way; ~90% develop it eventually): asymmetric ptosis and binocular diplopia. Pupils are spared (smooth muscle, not skeletal).
• Bulbar: dysarthria (nasal speech), dysphagia, fatigable chewing (jaw drops while eating), nasal regurgitation.
• Facial: "myasthenic snarl" – transverse smile from facial weakness.
• Neck and limb: proximal > distal; neck flexors commonly affected.
• Respiratory: diaphragm/intercostal weakness → myasthenic crisis.

Useful bedside signs:

• Cogan's lid twitch – brief upshoot of the upper lid when the eye returns to primary position from sustained downgaze.
• Peek sign – orbicularis fatigue: the sclera becomes visible after sustained lid closure.
• Curtain sign – manually elevating the more ptotic lid worsens ptosis on the other side.

High-yield: Pupillary reflexes are always normal in MG. Pupil involvement points elsewhere (botulism, third-nerve palsy, Lambert-Eaton can have mild autonomic features).

Ocular MG → generalised conversion occurs in ~50–80%, usually within the first 2 years. If weakness stays purely ocular beyond 2–3 years, generalisation is unlikely.

Diagnosis & investigation of choice

A stepwise approach:

Clinical suspicion → Bedside tests (ice-pack/edrophonium) → Serology (anti-AChR, then anti-MuSK) → Electrophysiology (RNS, then SFEMG) → CT/MRI chest for thymoma

Bedside tests

• Ice-pack test: Place ice over a ptotic lid for 2 minutes; improvement of ptosis by ≥2 mm is positive. Cold improves transmission by inhibiting acetylcholinesterase. Safe, simple — preferred when edrophonium is contraindicated, and especially useful for ocular MG.
• Edrophonium (Tensilon) test: Short-acting anticholinesterase (onset ~30 s, lasts ~5 min). Transient improvement in an objectively weak muscle (e.g., ptosis) is positive. Keep atropine and resuscitation ready (risk of bradycardia/asystole). Largely replaced by serology and the ice-pack test but still examined.

Serology

• Anti-AChR antibody – first-line; highly specific. If negative and clinical suspicion persists → anti-MuSK, then anti-LRP4.

Electrophysiology

Test	Finding in MG	Comment
Repetitive nerve stimulation (RNS)	Decremental response >10% in CMAP amplitude at low frequency (2–3 Hz)	Widely available; less sensitive in ocular MG
Single-fibre EMG (SFEMG)	Increased jitter ± blocking	Most sensitive test (>95%); not specific

High-yield: SFEMG is the most sensitive test for MG; RNS at 2–3 Hz showing a decremental response is the classic, most-tested electrophysiological finding. Contrast with Lambert-Eaton, where high-frequency (20–50 Hz) RNS or post-exercise gives an incremental response.

Imaging

• CT/MRI chest in every confirmed case to detect thymoma.

Always check thyroid function — autoimmune thyroid disease coexists in up to 10–15%.

Management & drug of choice

Treatment has four pillars: symptomatic, immunomodulatory (chronic), rapid (crisis), and surgical.

1. Symptomatic — drug of choice

• Pyridostigmine (long-acting anticholinesterase) is the first-line symptomatic drug. Typical 30–60 mg every 4–6 h. Muscarinic side-effects (cramps, diarrhoea, salivation) can be blunted with hyoscine/glycopyrrolate.
• Caution: anticholinesterases are less effective / may worsen MuSK-MG.

2. Chronic immunotherapy

• Corticosteroids (prednisolone) – mainstay. Start low and go slow: high starting doses can cause a transient steroid-induced exacerbation in the first 1–2 weeks.
• Steroid-sparing agents: azathioprine (first-line adjunct), mycophenolate, ciclosporin, tacrolimus, methotrexate.
• Refractory disease: rituximab (especially effective in MuSK-MG); eculizumab (complement C5 inhibitor) and efgartigimod (FcRn inhibitor) for refractory AChR-positive disease.

3. Crisis / rapid rescue

• Plasma exchange (PLEX) or IV immunoglobulin (IVIG) — equally effective for rapid improvement; used in crisis and pre-thymectomy.

4. Thymectomy

• Indicated for all thymomas. Also benefits non-thymomatous AChR-positive generalised MG in patients (especially <50–60 years) — improves outcomes and reduces steroid need (MGTX trial). Not routinely indicated for pure ocular or MuSK-MG.

High-yield: Pyridostigmine = symptomatic DOC. Thymectomy is mandatory if a thymoma is present, regardless of MG severity. PLEX/IVIG are the rapid rescue therapies in crisis.

Myasthenic crisis vs cholinergic crisis

A classic, frequently tested differentiation. Myasthenic crisis = respiratory failure from MG itself (under-treatment/infection/surgery). Cholinergic crisis = weakness from anticholinesterase overdose (excess ACh → depolarising block).

Feature	Myasthenic crisis	Cholinergic crisis
Cause	Disease worsening, infection, drugs, missed meds	Anticholinesterase overdose
Pupils	Normal / large	Small (miosis)
Secretions	Normal/dry	Excess salivation, lacrimation, bronchorrhoea
GI	Normal	Diarrhoea, cramps, vomiting
Muscles	Weak	Weak + fasciculations
Heart rate	Tachycardia	Bradycardia
Edrophonium test	Improves	Worsens weakness

High-yield: Cholinergic crisis = SLUDGE/DUMBELS (muscarinic excess) + miosis + fasciculations + bradycardia. Treatment of myasthenic crisis = secure airway/ventilation + PLEX or IVIG + treat trigger; withhold anticholinesterases temporarily.

Mnemonic for cholinergic excess — DUMBELS: Diarrhoea, Urination, Miosis, Bradycardia/Bronchorrhoea, Emesis, Lacrimation, Salivation.

Drugs that worsen MG (high-yield list)

Mnemonic "A PQ" antibiotics + others: Aminoglycosides, Penicillamine (can induce MG), Quinolones/quinine/quinidine; also macrolides, beta-blockers, magnesium sulphate (a classic obstetric pitfall), procainamide, calcium-channel blockers, neuromuscular blockers, and statins.

High-yield: IV magnesium sulphate can precipitate myasthenic crisis — avoid in eclampsia management of a myasthenic mother. Penicillamine is the classic drug-induced MG.

Complications

• Myasthenic crisis – neuromuscular respiratory failure needing ventilation; the leading cause of mortality.
• Aspiration pneumonia from bulbar weakness.
• Treatment-related: chronic steroid morbidity, immunosuppression-related infection, cholinergic crisis.
• Transient neonatal MG – maternal IgG crosses the placenta → hypotonia, poor feeding, weak cry in the neonate; self-limiting over 2–4 weeks as maternal antibody clears.

Key differentials

Condition	Distinguishing feature
Lambert-Eaton myasthenic syndrome (LEMS)	Pre-synaptic; anti-VGCC antibodies; paraneoplastic (small-cell lung cancer); proximal weakness that improves with exercise (facilitation); incremental RNS at high frequency; areflexia + autonomic features
Botulism	Descending paralysis, fixed dilated pupils, prominent autonomic features; incremental RNS
Guillain-Barré / Miller-Fisher	Areflexia, ascending weakness, albuminocytological dissociation
Thyroid eye disease / mitochondrial (CPEO)	Ophthalmoplegia but no fatigability, no decrement
Congenital myasthenic syndromes	Onset in infancy, no antibodies, genetic

High-yield: LEMS is the mirror image of MG — pre-synaptic, VGCC antibodies, facilitation on exercise, incremental RNS, associated with small-cell lung cancer.

Recently asked / exam angle

• Single best test: SFEMG (most sensitive); RNS decrement at 2–3 Hz is the classic answer when "investigation of choice on EMG" is asked.
• Bedside: ice-pack test for ptosis (≥2 mm improvement = positive) — increasingly favoured over edrophonium.
• Antibody numbers: anti-AChR ~85% generalised, ~50% ocular; anti-MuSK in seronegative disease.
• Crisis differentiation table (myasthenic vs cholinergic) — pupils, secretions, fasciculations, edrophonium response are the discriminators.
• Drug pitfalls: magnesium sulphate, aminoglycosides, penicillamine (drug-induced MG).
• Thymoma: mandatory chest CT; thymectomy indications (MGTX trial).
• MuSK-MG: IgG4, prominent bulbar/respiratory disease, poor response to pyridostigmine, responds to rituximab.
• Newest agents: eculizumab (anti-C5), efgartigimod (FcRn blocker) for refractory disease.
• Pupils spared is a near-universal single-line MCQ.

Rapid revision

1. MG = post-synaptic, antibody-mediated NMJ disorder; hallmark = fatigable weakness worse with activity.
2. Anti-AChR in ~85% generalised, ~50% ocular; anti-MuSK in seronegative (IgG4).
3. Pupils are spared; no sensory loss, reflexes preserved.
4. Ice-pack test ≥2 mm ptosis improvement = positive; edrophonium (Tensilon) transiently improves weakness.
5. SFEMG most sensitive; RNS at 2–3 Hz → decremental response is classic.
6. Pyridostigmine = symptomatic DOC; steroids + steroid-sparing agents for chronic control.
7. PLEX or IVIG for myasthenic crisis (equally effective); secure the airway first.
8. Thymoma in 10–15% → always CT chest; thymectomy mandatory if thymoma present.
9. Cholinergic crisis: miosis, fasciculations, bradycardia, excess secretions; edrophonium worsens it.
10. Worsening drugs: aminoglycosides, fluoroquinolones, beta-blockers, magnesium, penicillamine (drug-induced MG).
11. LEMS is pre-synaptic: VGCC antibodies, exercise facilitation, incremental RNS, small-cell lung cancer.
12. Transient neonatal MG from transplacental maternal IgG resolves in 2–4 weeks.