Myasthenia Gravis & NMJ Disorders

What You'll Learn

MG: autoimmune postsynaptic NMJ disorder; AChR Ab (~85%), MuSK Ab (5–8%), LRP4 Ab (1–2%), seronegative (5–10%); fatigable weakness — worse with activity, better with rest
MuSK MG: bulbar/facial/respiratory predominance; NO thymic pathology; POOR response to pyridostigmine; rituximab is preferred immunotherapy; complement inhibitors are not expected to be effective because MuSK antibodies are IgG4-mediated (IgG4 does not fix complement)
Diagnosis: SFEMG is most sensitive test (~95–99%); RNS shows ≥10% decrement at 2–3 Hz; AChR Ab is most specific serologic test; CT chest is recommended at diagnosis to evaluate for thymoma
Crisis: respiratory failure requiring intubation; monitor FVC — intubate if FVC <15 mL/kg (or <1 L) or NIF less negative than −20 to −30 cmH₂O; the “20/20/20 rule” is one mnemonic but more conservative thresholds (FVC <15) are often cited; trend matters most; treat with IVIg or PLEX (equally effective)
Medications to AVOID: aminoglycosides, fluoroquinolones, beta-blockers, calcium channel blockers (CCBs), magnesium, D-penicillamine, hydroxychloroquine, immune checkpoint inhibitors, botulinum toxin; use with caution: statins (less robust evidence), phenytoin (case reports)
LEMS: presynaptic NMJ disorder; P/Q-type VGCC antibodies; triad = proximal weakness + areflexia + autonomic dysfunction; ~60% have SCLC; incremental response ≥60% on high-frequency RNS (AANEM current standard; historical threshold was 100%, less sensitive); treat with 3,4-DAP
Botulism: presynaptic blockade (SNARE cleavage); descending paralysis + autonomic dysfunction + large unreactive pupils; treat with antitoxin
New therapies: C5 complement inhibitors (eculizumab, ravulizumab, zilucoplan) — adult AChR Ab-positive gMG; rozanolixizumab (Rystiggo, FcRn inhibitor) — adult AChR Ab-positive OR MuSK Ab-positive gMG; efgartigimod (Vyvgart / Vyvgart Hytrulo, FcRn inhibitor) — broader adult gMG indication regardless of antibody serotype after May 2026 label expansion

HighYield Pearls

Fatigable weakness, worse with activity/evening/heat, ocular onset in 50–65%: classic MG presentation — ptosis + diplopia + fluctuating bulbar/proximal weakness; ice pack test improves ptosis ≥2 mm in 2 min
MuSK MG = bulbar/facial/tongue atrophy phenotype: POOR response to pyridostigmine, GOOD response to rituximab; complement inhibitors NOT effective (IgG4 antibody does not fix complement)
CT chest is mandatory in every newly diagnosed AChR+ MG: thymoma in 10–15%; thymectomy benefits non-thymomatous AChR+ generalized MG age 18–65 (MGTX trial)
SFEMG = most sensitive (~95–99%), shows increased jitter; RNS 2–3 Hz decrement ≥10%: AChR Ab is most specific; edrophonium (Tensilon) is largely obsolete
MG crisis — intubate based on trend, not absolute number: FVC <15–20 mL/kg, NIF less negative than −30, MEP <40; treat with IVIG or PLEX (equally effective); always hunt the trigger (infection, surgery, offending drug)
Drugs that exacerbate MG: aminoglycosides, fluoroquinolones, macrolides (esp telithromycin), β-blockers, CCBs, magnesium (IV Mg in pre-eclampsia is high-risk), D-penicillamine, hydroxychloroquine, procainamide, quinine, immune checkpoint inhibitors
LEMS = proximal lower-limb weakness + areflexia + autonomic (dry mouth): reflexes/strength POTENTIATE after 10 sec exercise; low baseline CMAP with ≥60% increment on high-frequency RNS; ~60% have SCLC — screen with chest CT and re-screen at intervals
Botulism = DESCENDING flaccid paralysis + DILATED unreactive pupils + dry mouth + ileus: infant = honey/intestinal colonization → BabyBIG; adult/wound/foodborne → equine antitoxin; supportive ICU
Congenital myasthenic syndromes — pick the right drug: DOK7 and COLQ (slow-channel) → ephedrine/albuterol (AVOID pyridostigmine, worsens); ChAT → pyridostigmine; slow-channel → fluoxetine or quinidine
New targeted therapies for gMG — harmonized indications: C5 complement inhibitors (eculizumab, ravulizumab, zilucoplan) = adult AChR Ab-positive gMG; rozanolixizumab (Rystiggo) = adult AChR Ab-positive OR MuSK Ab-positive gMG; efgartigimod (Vyvgart / Vyvgart Hytrulo) = broader adult gMG regardless of antibody serotype after May 2026 label expansion

🔍 Quick ReferenceClinical · Electrodiagnostic · Antibody / treatment

Clinical phenotype

Fatigable ptosis + diplopia worse in the evening, ice pack improves ptosis → Myasthenia gravis (ocular/generalized)
Cogan lid twitch / sustained upgaze fatigue / nasal voice + jaw fatigue chewing → Myasthenia gravis (bulbar)
Bulbar predominance + tongue atrophy + facial wasting + poor pyridostigmine response → MuSK MG
Proximal lower-limb weakness + dry mouth + areflexia that improves after brief exercise (post-exercise facilitation) → LEMS (anti-VGCC P/Q-type, SCLC)
Descending flaccid paralysis + fixed dilated pupils + ileus + dry mouth in an infant fed honey → Infant botulism
Neonate of an MG mother with transient hypotonia/feeding difficulty resolving in weeks → Neonatal transient MG (passive AChR Ab transfer)
Neonatal apneic episodes that respond to pyridostigmine → ChAT congenital myasthenic syndrome
Limb-girdle weakness in a child, worsens with pyridostigmine, improves with ephedrine/albuterol → DOK7 congenital myasthenic syndrome

Electrodiagnostic / labs

RNS 2–3 Hz decrement >10% with normal baseline CMAP → Postsynaptic disorder (MG)
Increased jitter and blocking on single-fiber EMG → Most sensitive test for MG (~95–99%)
Low baseline CMAP + ≥60% increment after 10-sec brief exercise or 50 Hz RNS → LEMS
Tensilon / edrophonium transient improvement in ptosis → MG (historical; rarely used now)
Ice pack ≥2 mm ptosis improvement in 2 min → Ocular MG bedside test
EMG facilitation with brief exercise (less dramatic than LEMS) → Botulism

Antibody / treatment pearls

Anti-AChR antibody → 85% of generalized MG, 50% of pure ocular MG; thymoma in 10–15% — CT chest mandatory
Anti-MuSK antibody (IgG4) → Bulbar predominance; rituximab is preferred; complement inhibitors NOT effective (IgG4 does not fix complement)
Anti-LRP4 antibody → 1–3% of MG; generally milder phenotype
Anti-VGCC P/Q-type antibody → LEMS — treat with 3,4-diaminopyridine (amifampridine); pyridostigmine adjunct; treat SCLC
Eculizumab / ravulizumab / zilucoplan (complement C5) → Adult AChR Ab-positive generalized MG (meningococcal vaccination required)
Rozanolixizumab (Rystiggo, FcRn antagonist) → Adult AChR Ab-positive OR MuSK Ab-positive generalized MG
Efgartigimod (Vyvgart / Vyvgart Hytrulo, FcRn antagonist) → Adult generalized MG — broader indication regardless of antibody serotype after May 2026 label expansion
BabyBIG (human botulism IVIG) for infants; equine antitoxin for adult/wound/foodborne → Botulism antitoxin
Drugs that exacerbate MG → Aminoglycosides, fluoroquinolones, macrolides, β-blockers, CCBs, Mg, D-penicillamine, immune checkpoint inhibitors

NMJ Physiology

Normal Neuromuscular Transmission

Presynaptic terminal: ACh synthesized from choline + acetyl-CoA by choline acetyltransferase (ChAT); packaged into vesicles by vesicular ACh transporter (VAChT)
Action potential arrival → Ca²⁺ influx through P/Q-type VGCCs → vesicle fusion via SNARE complex (synaptobrevin, SNAP-25, syntaxin) → ACh release into synaptic cleft
Synaptic cleft: acetylcholinesterase (AChE) rapidly hydrolyzes ACh; choline recycled back into nerve terminal
Postsynaptic: ACh binds nicotinic AChRs on muscle endplate → Na⁺ influx → endplate potential (EPP) → if EPP exceeds threshold, muscle fiber action potential fires
Safety factor: normal EPP is ~3–4× greater than threshold needed to fire — ensures reliable transmission even with physiologic variability

Feature	Presynaptic NMJ Disorders	Postsynaptic NMJ Disorders
Mechanism	Impaired ACh release	Impaired ACh receptor function
Safety factor reduced by	Fewer quanta released per impulse	Reduced postsynaptic response per quantum
Prototypes	LEMS, botulism	Myasthenia gravis
RNS at low frequency	Decrement (small baseline CMAP)	Decrement (normal baseline CMAP)
RNS at high frequency	Incremental response (≥60% increment — AANEM current standard; historical threshold was 100%, less sensitive)	No increment
Reflexes	Diminished/absent (improve post-exercise)	Normal
Autonomic features	Common (LEMS, botulism)	Absent

💎 Board Pearl

The safety factor explains why NMJ disorders cause fatigable weakness — with repeated stimulation, fewer quanta are released (normal presynaptic depletion), but if the safety factor is already reduced, EPP falls below threshold
P/Q-type VGCCs are the primary calcium channels at the NMJ presynaptic terminal — targeted in LEMS
SNARE complex is the target of botulinum toxin (cleaves SNAP-25/synaptobrevin) and tetanus toxin (cleaves synaptobrevin in inhibitory interneurons)

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