Myasthenia Gravis & NMJ Disorders
What Do You Need to Know?
- 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
- 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
Clinical phenotype
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 |
- 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)
Myasthenia Gravis — Classification & Antibodies
MGFA Clinical Classification
| Class | Description |
|---|
| I | Ocular only — ptosis, diplopia; no other weakness |
| II | Mild generalized — may have ocular symptoms |
| IIa | Predominantly limb/axial |
| IIb | Predominantly bulbar/respiratory |
| III | Moderate generalized |
| IIIa | Predominantly limb/axial |
| IIIb | Predominantly bulbar/respiratory |
| IV | Severe generalized |
| IVa | Predominantly limb/axial |
| IVb | Predominantly bulbar/respiratory |
| V | Intubation required (with or without mechanical ventilation) = myasthenic crisis |
Antibody Subtypes
| Feature | AChR Ab | MuSK Ab | LRP4 Ab | Seronegative |
|---|
| Frequency | ~85% of generalized MG (~85% generalized, ~50% pure ocular) | 5–8% | 1–2% | 5–10% |
| Antibody class | IgG1, IgG3 (complement-fixing) | IgG4 (non-complement-fixing) | IgG1, IgG2 | May have low-affinity AChR Ab |
| Demographics | Bimodal: F <40, M >60 | Young women (F ≫ M) | Variable | Variable |
| Clinical pattern | Ocular → generalized; limb + ocular predominant | Bulbar/facial/respiratory; neck/shoulder weakness; tongue/facial atrophy | Mild; often ocular or mild generalized | Similar to AChR Ab+ MG |
| Thymus | Hyperplasia (~65%); thymoma (~10–15%) | Normal — NO thymic pathology | Normal | May have hyperplasia |
| Pyridostigmine | Good response | Poor response (may worsen) | Variable | Variable |
| Thymectomy | Indicated (non-thymoma + thymoma) | NOT indicated | Not established | May benefit |
| Preferred immunotherapy | Standard immunotherapy | Rituximab (first-line after steroids) | Standard immunotherapy | Standard immunotherapy |
| Complement inhibitors | Approved (eculizumab, ravulizumab) | NOT effective (IgG4 → no complement) | Not studied | Not studied |
| Crisis risk | Moderate | High (respiratory predominance) | Low | Low–moderate |
Early-Onset vs Late-Onset AChR+ MG
| Feature | Early-Onset MG (<40 yr) | Late-Onset MG (>50 yr) |
|---|
| Sex | Female predominance (F:M 3:1) | Male predominance (M:F 2:1) |
| Thymus | Thymic hyperplasia (65–75%) | Thymoma (~15%); thymic involution |
| HLA association | HLA-B8, DR3 | HLA-B7, DR2 |
| Anti-striated muscle Ab | Rare | 85% if thymoma present |
- MuSK MG is the most board-tested subtype — remember: bulbar predominance, NO thymoma, POOR pyridostigmine response, rituximab preferred; complement inhibitors are not expected to be effective because MuSK antibodies are IgG4-mediated (IgG4 does not fix complement)
- ~50% of ocular MG patients are AChR Ab negative — but ~50% of “seronegative” patients convert to seropositive on repeat testing or with cell-based assay
- Thymoma-associated MG: more severe, older onset, higher AChR Ab titers, anti-striated muscle Ab in ~85%; thymectomy mandatory regardless of MG severity
- AChR binding Ab = most commonly ordered (~85% sensitive in generalized MG, only ~50% in ocular MG); AChR modulating Ab increases sensitivity when combined
- MuSK Ab is IgG4 — IgG4 does not fix complement, so complement inhibitors (eculizumab, ravulizumab, zilucoplan) are not expected to be effective in MuSK MG; the disease is “antibody-mediated” without complement deposition at the NMJ
- ~10–15% of MG patients have a thymoma; conversely, 30–50% of thymoma patients develop MG — CT chest is recommended at diagnosis to evaluate for thymoma
- Anti-striated muscle Ab (titin, ryanodine receptor) in a patient with MG = search for thymoma (~85% specificity)
- Purely ocular MG that remains ocular >2 years has <5% chance of generalizing
Diagnosis
Bedside & Serologic Tests
| Test | Method | Key Points |
|---|
| Ice pack test | Apply ice to closed eyelid ×2 min; assess ptosis improvement | Cooling inhibits AChE → more ACh available; ~80% sensitivity for ocular MG; no risk (unlike edrophonium) |
| Rest test | Eyes closed ×5 min; assess improvement | Supports fatigable weakness; nonspecific |
| Edrophonium (Tensilon) test | IV AChE inhibitor; rapid onset (~30 s), short duration (~5 min) | Largely withdrawn from US market (since ~2018); historical interest only on boards. Risk of bradycardia/bronchospasm; atropine must be at bedside; replaced by ice pack test + serology |
| AChR binding Ab | Radioimmunoassay | ~85% sensitive in generalized MG; ~50% in ocular MG; most specific serologic test (>99%) |
| MuSK Ab | Cell-based assay or RIA | Order if AChR Ab negative; 5–8% of MG |
| LRP4 Ab | Cell-based assay | 1–2% of MG; order after AChR and MuSK negative |
| Striational Ab (anti-titin, anti-RyR) | Immunofluorescence | Associated with thymoma — if positive, CT chest urgently; ~85% specificity for thymoma |
| CT chest | Imaging | Mandatory in ALL MG patients — screening for thymoma |
Electrophysiology: RNS vs SFEMG
| Feature | Repetitive Nerve Stimulation (RNS) | Single-Fiber EMG (SFEMG) |
|---|
| What it measures | Decrement in CMAP amplitude with repeated stimulation | Variability in time interval between 2 muscle fiber action potentials from same motor unit (jitter) |
| Technique | Stimulate motor nerve at 2–3 Hz; compare 1st and 4th/5th CMAP | Voluntary activation or stimulated; measure jitter in ≥20 fiber pairs |
| Positive result | ≥10% decrement between 1st and 4th/5th response | Increased jitter (>55 µs in most muscles) and/or blocking |
| Sensitivity — generalized MG | ~75–80% | ~95–99% |
| Sensitivity — ocular MG | ~30–50% | ~85–95% (frontalis/orbicularis oculi) |
| Specificity | High (when ≥10% decrement) | Low — increased jitter seen in any NMJ or myopathic process |
| Best muscles to test | Proximal: trapezius, deltoid, nasalis; test clinically weak muscles | Frontalis, orbicularis oculi, extensor digitorum communis |
| Post-exercise facilitation | Brief improvement in decrement after 10 s of exercise (repair of decrement) | Not applicable |
| Post-exercise exhaustion | Worsened decrement 2–5 min after exercise | Not applicable |
- SFEMG is the single most sensitive test for MG (~95–99%) but is NOT specific — increased jitter can occur in motor neuron disease, myopathy, and other NMJ disorders
- AChR Ab is the most specific test (>99%) — a positive result essentially confirms MG
- RNS decrement at 2–3 Hz: the 4th or 5th response is compared to the 1st — decrement is maximal at 3rd–4th stimulus (before mobilization store replenishes); must be ≥10% to be significant
- Post-exercise facilitation in MG: brief repair of decrement immediately after exercise; post-exercise exhaustion: worsened decrement 2–5 min later — test BOTH to increase sensitivity
- Ice pack test works because cold inhibits AChE → more ACh at NMJ; it does NOT work in non-NMJ causes of ptosis
- Edrophonium test is largely obsolete — replaced by ice pack test (safer) and serology
Treatment
Symptomatic Therapy
| Agent | Mechanism | Key Points |
|---|
| Pyridostigmine | Reversible AChE inhibitor → increases ACh at NMJ | First-line symptomatic therapy; dose 30–60 mg every 4–6 hours; typical max ~540 mg/day. Higher/more frequent dosing risks cholinergic crisis. Onset 30 min, peak 2 hr, duration 4–6 hr; side effects = SLUDGE (Salivation, Lacrimation, Urination, Diarrhea, GI cramping, Emesis); overdose → cholinergic crisis |
| Neostigmine | AChE inhibitor (parenteral) | Used intraoperatively or when PO not feasible; shorter duration than pyridostigmine |
Immunotherapy
| Agent | Mechanism | Onset | Key Points |
|---|
| Prednisone | Broad immunosuppression | 2–4 weeks | Most effective conventional immunotherapy; start low and titrate (risk of initial worsening at high doses — consider inpatient initiation for severe disease); long-term side effects limit use |
| Azathioprine | Purine synthesis inhibitor | 6–12 months | Steroid-sparing; check TPMT before starting (deficiency → life-threatening myelosuppression); monitor CBC, LFTs |
| Mycophenolate mofetil | Purine synthesis inhibitor | 6–12 months | Steroid-sparing; teratogenic; monitor CBC; RCTs did not show benefit at 3 months (but slow onset explains negative trials) |
| Rituximab | Anti-CD20 → B-cell depletion | 3–6 months (often faster, 1–3 months, in MuSK-MG) | Preferred for MuSK MG (often first-line IS); increasingly used early in AChR+ MG; risk of PML (rare), hepatitis B reactivation |
| Cyclosporine | Calcineurin inhibitor | 1–3 months | Fastest-onset steroid-sparing agent; nephrotoxicity, hypertension; alternative in refractory disease |
| Tacrolimus | Calcineurin inhibitor | 1–3 months | Similar to cyclosporine; may be better tolerated; less commonly used in Western countries |
Rapid Immunotherapy (Rescue / Bridge)
| Agent | Mechanism | Onset | Duration | Key Points |
|---|
| IVIg | Immunomodulation; Fc receptor blockade; accelerated IgG catabolism | Days to 1–2 weeks | 3–6 weeks | 0.4 g/kg/day ×5 days (total 2 g/kg); risk of aseptic meningitis, thrombosis, renal failure; check IgA level (anaphylaxis in IgA deficiency) |
| Plasma exchange (PLEX) | Removes circulating antibodies | Days | 2–4 weeks | 5 exchanges over 10–14 days; requires large-bore IV or central venous access; risk of hypotension, coagulopathy, line infection; equally effective as IVIg for crisis |
Novel Targeted Therapies
| Agent | Mechanism | Target | Key Points |
|---|
| Eculizumab | Anti-C5 monoclonal antibody | Terminal complement (C5) | Blocks membrane attack complex (MAC) formation; approved for adult AChR Ab-positive generalized MG; induction 900 mg IV weekly ×4, then 1200 mg in week 5, then 1200 mg IV q2 weeks maintenance; risk of Neisseria meningitis → MenACWY + MenB vaccines required ≥2 weeks before first dose; very expensive |
| Ravulizumab | Anti-C5 (long-acting) | Terminal complement (C5) | Adult AChR Ab-positive generalized MG; same mechanism as eculizumab but longer half-life → IV q8 weeks; same meningococcal risk |
| Zilucoplan | C5 inhibitor (peptide) | Terminal complement (C5) | SC daily; approved for adult AChR Ab-positive generalized MG; smaller molecule; same meningococcal risk |
| Efgartigimod (Vyvgart / Vyvgart Hytrulo) | FcRn inhibitor | Neonatal Fc receptor (FcRn) | Blocks IgG recycling → accelerates IgG degradation → lowers pathogenic antibodies; IV q1 week ×4 (cyclic) or SC (+ hyaluronidase, Vyvgart Hytrulo); broader adult gMG indication regardless of antibody serotype after May 2026 label expansion |
| Rozanolixizumab (Rystiggo) | FcRn inhibitor | Neonatal Fc receptor (FcRn) | SC injection; approved for adult AChR Ab-positive OR MuSK Ab-positive generalized MG; similar mechanism to efgartigimod |
Thymectomy
| Feature | Details |
|---|
| MGTX Trial (NEJM 2016) | RCT: thymectomy + prednisone vs prednisone alone in AChR Ab+ non-thymomatous generalized MG; thymectomy group had lower prednisone requirements, better QMG scores, fewer immunosuppressants at 3 years |
| Indications | ALL thymoma-associated MG (mandatory); AChR Ab+ generalized MG age 18–65 (MGTX criteria); consider in AChR Ab+ MG not controlled with immunotherapy |
| NOT indicated | MuSK MG (no thymic pathology); isolated ocular MG (debated); LRP4 MG; seronegative MG (limited evidence) |
| Timing | Optimize MG control first; avoid surgery during crisis; benefit may take 1–3 years to manifest |
| Approach | Extended transsternal or robotic/VATS thymectomy; must remove ALL thymic tissue |
- Initial worsening on prednisone: start low (10–20 mg) and titrate up over weeks — high-dose initiation can trigger myasthenic exacerbation; consider inpatient initiation for severe disease
- FcRn inhibitors (efgartigimod, rozanolixizumab) lower ALL IgG subclasses, not just pathogenic antibodies — monitor for infection risk
- Complement inhibitors are effective in AChR Ab+ MG (complement-mediated) — they are not expected to be effective in MuSK MG because MuSK antibodies are IgG4, which does not fix complement
MG in Pregnancy
- Course: ~40% worsen (most often in the 1st trimester or postpartum); ~30% stable; ~30% improve. Highest risk in the first year postpartum.
- Safe: pyridostigmine, IVIG, PLEX; prednisone in 2nd/3rd trimester (1st-trimester high-dose steroids carry low absolute cleft-palate risk — do not withhold if needed).
- Avoid: methotrexate (Category X), mycophenolate (teratogenic). Azathioprine and cyclosporine acceptable when benefit outweighs risk.
- Pre-eclampsia: do NOT use IV magnesium sulfate — precipitates myasthenic crisis. Use levetiracetam or phenytoin for seizure prophylaxis instead.
- Delivery: vaginal delivery preferred; the second stage (smooth-muscle uterine contraction is unaffected, but voluntary expulsive effort fatigues) may need assisted/instrumental delivery. Regional anesthesia preferred over general (avoid non-depolarizing NMBs).
- Transient neonatal MG: 10–20% from transplacental maternal anti-AChR IgG → floppy/poor-feeding neonate; resolves spontaneously over 2–4 weeks; manage with pyridostigmine and supportive care.
- MGTX Trial: thymectomy is now Level 1 evidence for AChR Ab+ generalized MG — know this trial by name for boards
- Check TPMT before azathioprine — deficiency causes life-threatening myelosuppression
- Meningococcal vaccination is MANDATORY before starting any complement inhibitor (eculizumab, ravulizumab, zilucoplan) due to Neisseria meningitidis risk
- MuSK MG treatment ladder: steroids → rituximab (preferred over azathioprine/mycophenolate); pyridostigmine may worsen symptoms; NO thymectomy; complement inhibitors not expected to be effective (IgG4-mediated)
Myasthenic Crisis
Overview & Triggers
| Feature | Details |
|---|
| Definition | MG exacerbation requiring intubation/mechanical ventilation (MGFA Class V) |
| Incidence | ~15–20% of MG patients experience ≥1 crisis |
| Mortality | ~5% with modern ICU care (down from ~40% in pre-ICU era) |
| Common triggers | Infection (#1 trigger), surgery, medication changes, tapering immunotherapy, pregnancy/postpartum, emotional stress |
| Highest risk period | First 2–3 years after diagnosis |
Medications to AVOID in MG
| Drug Class | Examples | Mechanism of Worsening |
|---|
| Aminoglycosides | Gentamicin, tobramycin, amikacin | Presynaptic: decrease ACh release; postsynaptic: block AChR ion channel |
| Fluoroquinolones | Ciprofloxacin, levofloxacin, moxifloxacin | Pre- and postsynaptic NMJ blockade; FDA black box warning for MG |
| Macrolides | Azithromycin, erythromycin, telithromycin | NMJ blockade; telithromycin has FDA black box warning specifically for MG — may cause fatal exacerbation |
| Beta-blockers | Propranolol, atenolol, timolol (eye drops) | Curare-like postsynaptic NMJ blockade; even topical ophthalmic beta-blockers can worsen MG |
| Magnesium | IV magnesium sulfate | Presynaptic: competes with Ca2+ → reduces ACh release; dangerous in eclampsia with coexisting MG |
| D-Penicillamine | Penicillamine | Induces autoimmune MG (AChR Ab production); resolves after discontinuation (weeks–months) |
| Immune checkpoint inhibitors | Nivolumab, pembrolizumab, ipilimumab | Immune dysregulation → de novo MG or unmasking; can be fulminant with concurrent myocarditis; high mortality |
| Botulinum toxin | OnabotulinumtoxinA, abobotulinumtoxinA | Presynaptic blockade at NMJ — labels warn that patients with NMJ disorders (MG, LEMS) are at increased risk of systemic weakness, dysphagia, and respiratory compromise. Avoid unless a compelling specialist-supervised indication is present (not an absolute contraindication) |
| Neuromuscular blockers | Succinylcholine, vecuronium, rocuronium | MG patients are resistant to succinylcholine (depolarizing — higher dose may be needed due to fewer AChRs); markedly HYPERSENSITIVE to non-depolarizing agents (vecuronium, rocuronium — use ~10–50% of normal dose) |
| Calcium channel blockers (CCBs) | Verapamil, diltiazem, nifedipine | Presynaptic: reduce Ca2+ influx → reduce ACh release |
| Hydroxychloroquine / chloroquine | Hydroxychloroquine, chloroquine | Postsynaptic NMJ blockade; usually mild, resolves after discontinuation |
| Others | Quinine, quinidine, procainamide, lithium | Various NMJ-blocking mechanisms |
| Use with caution (not absolute-avoid) | Statins (less robust evidence), phenytoin (case reports) | Reports of MG worsening or unmasking; weigh risk/benefit, monitor closely — not contraindicated |
Respiratory Monitoring & the 20/20/20 Rule
| Parameter | Threshold for Intubation | Notes |
|---|
| FVC | <15 mL/kg (or <1 L) | Normal FVC ~60–70 mL/kg; serial monitoring q2–4h; trend more important than single value; 20/20/20 is one mnemonic, but more conservative thresholds (FVC <15) are often cited |
| NIF (MIP) | Less negative than −20 to −30 cmH2O | Measures inspiratory muscle strength; −15 is worse than −25 (less negative = weaker) |
| MEP | <40 cmH2O | Measures expiratory force / cough strength |
- Intubation thresholds: FVC <15 mL/kg (or <1 L), NIF less negative than −20 to −30 cmH2O, or MEP <40 cmH2O — do NOT wait for ABG changes (late finding). The 20/20/20 mnemonic is widely taught, but more conservative thresholds (FVC <15) are often cited; trend matters most
- Management: ICU admission → serial FVC/NIF q2–4h → IVIg or PLEX (equally effective) → identify and treat trigger → optimize long-term immunotherapy after stabilization
- Hold pyridostigmine during intubation — reduces secretions and eliminates variable of cholinergic crisis; restart when extubated
- Do NOT initiate high-dose steroids acutely in crisis — can worsen weakness in first 1–2 weeks; stabilize with PLEX/IVIg first
Myasthenic Crisis vs Cholinergic Crisis
| Feature | Myasthenic Crisis | Cholinergic Crisis |
|---|
| Cause | Disease exacerbation (undertreated) | AChE inhibitor overdose (pyridostigmine excess) |
| Weakness | Worsening MG weakness | Weakness from depolarization block |
| Pupils | Normal | Miotic (small) |
| Secretions | Normal | Excessive (SLUDGE) — salivation, lacrimation, diarrhea |
| Fasciculations | Absent | Present (nicotinic excess) |
| Response to edrophonium | Improves (more ACh helps) | Worsens (ACh excess) |
| Treatment | IVIg or PLEX; intubation PRN | Stop AChE inhibitor; atropine for muscarinic symptoms; intubation PRN |
- Infection is the #1 trigger for myasthenic crisis — but treat carefully because aminoglycosides and fluoroquinolones are contraindicated in MG
- Do NOT rely on pulse oximetry or ABG to decide on intubation — by the time SpO2 drops or CO2 rises, the patient is in extremis; use serial FVC and NIF
- Cholinergic crisis is now rare with modern dosing but a classic board question — key differentiator is SLUDGE symptoms + fasciculations
- D-penicillamine causes a true autoimmune MG with AChR antibodies — resolves weeks to months after discontinuation
- Telithromycin has an FDA black box warning specifically for MG — may cause fatal exacerbation
- Checkpoint inhibitor-induced MG: can present with fulminant crisis + myocarditis + elevated CK (overlap syndrome) — hold immunotherapy, give steroids + IVIg/PLEX
Lambert-Eaton Myasthenic Syndrome (LEMS)
Pathophysiology & Clinical Features
| Feature | Details |
|---|
| Mechanism | Antibodies against P/Q-type VGCCs on presynaptic motor nerve terminal → decreased Ca2+ influx → reduced ACh vesicle release |
| Antibody | P/Q-type VGCC Ab (~85–90%); SOX1 Ab (paraneoplastic marker, ~65% of SCLC-LEMS) |
| Cancer association | ~60% paraneoplastic (SCLC); ~40% autoimmune; VGCCs expressed on SCLC tumor → immune cross-reactivity |
| Clinical triad | Proximal weakness + hyporeflexia/areflexia + autonomic dysfunction |
| Weakness pattern | Proximal > distal; legs > arms; improves transiently with initial exercise (post-exercise facilitation) |
| Reflexes | Absent at rest; reappear after brief exercise (post-exercise facilitation = pathognomonic) |
| Autonomic | Dry mouth (#1 symptom, often earliest), constipation, erectile dysfunction, orthostatic hypotension, anhidrosis |
| Ocular/bulbar | Mild compared to MG — mild ptosis may occur but diplopia and severe dysphagia are less prominent |
MG vs LEMS Comparison
| Feature | Myasthenia Gravis | LEMS |
|---|
| NMJ defect site | Postsynaptic (AChR) | Presynaptic (VGCC) |
| Antibody | AChR, MuSK, or LRP4 | P/Q-type VGCC |
| Weakness pattern | Ocular → bulbar → generalized; fatigable | Proximal legs > arms; improves briefly with activity |
| Reflexes | Normal | Absent (improve post-exercise) |
| Autonomic | Absent | Present (dry mouth, constipation, ED) |
| Pupils | Normal | May be sluggish |
| Ocular involvement | Very common (~85%); often presenting feature | Mild or absent; rarely presenting feature |
| Cancer | Thymoma (10–15%) | SCLC (~60%) |
| Baseline CMAP | Normal amplitude | Low amplitude |
| RNS (2–3 Hz) | Decrement ≥10% | Decrement; low baseline CMAP |
| RNS (20–50 Hz) or post-exercise | No significant increment | Incremental response ≥60% (AANEM current standard; historical threshold was 100%, less sensitive; often ≥200% in classic cases) |
| SFEMG | Increased jitter + blocking | Increased jitter + blocking (improves at higher firing rates) |
| Treatment | Pyridostigmine, immunotherapy, thymectomy | 3,4-DAP, treat underlying cancer, immunotherapy |
Screening & Treatment
| Feature | Details |
|---|
| DELTA-P score | Predicts SCLC in LEMS: Dysarthria, Erectile dysfunction, Loss of weight, Tobacco use, Age >50, Karnofsky Performance; score ≥3 → high probability of SCLC |
| Cancer screening | CT chest at diagnosis; if negative, repeat q6 months ×2 years; PET/CT if high clinical suspicion; SOX1 Ab supports paraneoplastic etiology |
| 3,4-DAP (amifampridine) | Blocks presynaptic K+ channels → prolongs action potential → more Ca2+ influx → increased ACh release; first-line symptomatic therapy; FDA-approved for LEMS (Firdapse, FDA-approved 2018) |
| Pyridostigmine | May add as adjunct (modest benefit — limited ACh release to work with) |
| Immunotherapy | IVIg, PLEX, prednisone, azathioprine for autoimmune LEMS; treat tumor for paraneoplastic LEMS |
- Post-exercise facilitation of reflexes is pathognomonic for LEMS — test by having patient contract quadriceps for 10 seconds, then recheck patellar reflex
- Dry mouth is often the first autonomic symptom in LEMS — may precede weakness by months
- If you diagnose LEMS, you MUST screen for SCLC — cancer treatment often improves neurologic symptoms
- Low baseline CMAP that increases ≥60% at 50 Hz RNS (or post-exercise) = LEMS (AANEM current standard; historical threshold was 100%, less sensitive); in MG the baseline CMAP is normal
- 3,4-DAP works by blocking K+ channels (prolongs presynaptic depolarization) — NOT by blocking AChE — this is a common board trap
- P/Q-type VGCC Ab is diagnostic but NOT specific for cancer — use SOX1 Ab to distinguish paraneoplastic from autoimmune LEMS
- LEMS can coexist with cerebellar degeneration (shared P/Q VGCC target on Purkinje cells) — both are paraneoplastic in SCLC
Other NMJ Disorders
Botulism
| Feature | Details |
|---|
| Mechanism | Clostridium botulinum toxin cleaves SNARE proteins (SNAP-25, synaptobrevin) → blocks presynaptic ACh vesicle fusion/release |
| Types | Foodborne (preformed toxin in canned foods); wound (IV drug users, black tar heroin); infant (spore ingestion, honey — age <1 yr); iatrogenic (cosmetic Botox) |
| Classic presentation | Descending paralysis + autonomic dysfunction + bulbar weakness |
| Pupils | Fixed, dilated (mydriasis) — key distinguishing feature from MG and GBS |
| Key features | Descending (cranial → arms → legs → diaphragm); symmetric; NO sensory loss; dry mouth, constipation, urinary retention; alert mental status (toxin does not cross BBB) |
| EMG | Low CMAP amplitude; incremental response at high-frequency RNS (similar to LEMS but often <100%); SFEMG shows increased jitter |
| Diagnosis | Toxin assay in serum, stool, or wound; mouse bioassay is gold standard |
| Treatment | Antitoxin (equine heptavalent for adults; BabyBIG/botulism immune globulin for infants); wound botulism: antibiotics (penicillin G or metronidazole) + debridement; infant botulism: do NOT give antibiotics (lysis releases toxin) |
Organophosphate & Nerve Agent Poisoning
| Feature | Details |
|---|
| Mechanism | Irreversible AChE inhibition → ACh excess at muscarinic AND nicotinic receptors |
| Muscarinic effects (SLUDGE + killer Bs) | Salivation, Lacrimation, Urination, Diarrhea, GI cramping, Emesis; Bradycardia, Bronchospasm, Bronchorrhea |
| Nicotinic effects | Fasciculations, muscle weakness, paralysis, tachycardia (initial sympathetic surge) |
| CNS effects | Seizures, altered mental status, coma |
| Pupils | Miotic (pinpoint) — opposite of botulism |
| Treatment | Atropine (blocks muscarinic effects; titrate to dry secretions) + pralidoxime (2-PAM) (reactivates AChE if given before “aging”; must give within 24–48h); benzodiazepines for seizures |
| Intermediate syndrome | Proximal weakness 24–96h after exposure; respiratory failure risk; due to persistent NMJ blockade after cholinergic symptoms resolve |
Congenital Myasthenic Syndromes (CMS)
| Type / Gene | Location | Key Features | Treatment |
|---|
| ChAT deficiency | Presynaptic | Episodic apnea in infancy; normal between episodes; triggered by infection/stress | Pyridostigmine + 3,4-DAP |
| AChE deficiency (COLQ) | Synaptic | Slow pupillary light response; repetitive CMAP after single stimulus; AChE inhibitors CONTRAINDICATED (worsen) | Ephedrine or salbutamol; AVOID AChEi |
| AChR deficiency (CHRNE) | Postsynaptic | Most common CMS; reduced AChR number; generalized weakness from birth | Pyridostigmine + 3,4-DAP |
| Slow-channel CMS | Postsynaptic | Gain-of-function AChR mutation → prolonged channel opening → endplate myopathy; selective hand/forearm/neck extensor weakness; repetitive CMAP; AD inheritance | Fluoxetine first-line (quinidine largely unavailable in US); both are long-lived open-channel blockers; AVOID AChEi (worsens) |
| Fast-channel CMS | Postsynaptic | Loss-of-function AChR mutation → shortened channel opening; severe weakness | Pyridostigmine + 3,4-DAP |
| DOK7 CMS | Postsynaptic (signaling) | Limb-girdle pattern; proximal weakness; waddling gait; childhood onset; AChEi worsens | Ephedrine or salbutamol; AVOID AChEi |
| Rapsyn deficiency | Postsynaptic | AChR clustering defect; neonatal ptosis, feeding difficulty, arthrogryposis; episodic crises | Pyridostigmine + 3,4-DAP |
Drug-Induced Myasthenia
| Drug | Mechanism | Outcome |
|---|
| D-Penicillamine | Induces AChR antibody production | True autoimmune MG; resolves after drug discontinuation (weeks–months) |
| Immune checkpoint inhibitors | Anti-PD-1/PD-L1/CTLA-4 immune dysregulation | De novo MG or unmasking subclinical MG; can be fulminant with concurrent myocarditis + myositis (overlap); AChR Ab+ in ~40–60% (variable across series); high mortality |
| Interferon-α | Immune modulation | MG with AChR antibodies; resolves after discontinuation |
| Chloroquine/hydroxychloroquine | Postsynaptic NMJ blockade | Usually mild; resolves after discontinuation |
NMJ Toxins & Poisons
| Agent | NMJ Target | Mechanism | Key Features |
|---|
| Botulinum toxin | Presynaptic | Cleaves SNARE proteins (SNAP-25) | Descending paralysis, mydriasis, autonomic dysfunction |
| Tetanus toxin | Presynaptic (inhibitory interneurons) | Cleaves synaptobrevin in Renshaw cells/inhibitory neurons | Spastic paralysis, trismus, opisthotonus; ascending |
| Organophosphates | Synaptic (AChE) | Irreversible AChE inhibition → ACh excess | SLUDGE + nicotinic + CNS symptoms; miotic pupils |
| Black widow spider (α-latrotoxin) | Presynaptic | Massive ACh release then depletion | Pain/cramping → weakness; abdominal rigidity |
| Tick paralysis | Presynaptic | Neurotoxin in tick saliva reduces ACh release | Ascending paralysis (mimics GBS); resolves with tick removal |
| Curare (tubocurarine) | Postsynaptic | Competitive AChR antagonist | Flaccid paralysis; reversed by AChE inhibitors (neostigmine) |
| Succinylcholine | Postsynaptic | Depolarizing AChR agonist → sustained depolarization | Phase I: fasciculations then block; Phase II: non-depolarizing block |
| Snake venoms (α-bungarotoxin) | Postsynaptic | Irreversible AChR binding | Elapid envenomation; respiratory paralysis |
- Tick paralysis mimics Guillain-Barré syndrome (ascending paralysis, areflexia) — always check for a tick in the scalp; complete recovery after removal
- In CMS, AChE inhibitors can be harmful in slow-channel syndrome, COLQ deficiency, and DOK7 — genetic diagnosis is essential before treatment
- Checkpoint inhibitor MG can be fatal — occurs in ~1% of patients on anti-PD-1 therapy; may present with concurrent myositis and myocarditis (overlap syndrome)
- Botulism pupils = dilated (mydriasis); Organophosphate pupils = miotic (pinpoint) — classic board differentiator
- Pralidoxime must be given before “aging” — once the organophosphate-AChE bond ages (24–48h), the enzyme cannot be reactivated
- Infant botulism: do NOT give antibiotics (lysis of C. botulinum releases more toxin); give BabyBIG (botulism immune globulin); honey exposure is the classic association
- Tetanus toxin targets inhibitory interneurons (blocks glycine/GABA release) → spastic paralysis; botulinum toxin targets motor neurons → flaccid paralysis
- AChEi WORSENS three CMS subtypes: slow-channel, AChE/COLQ deficiency, and DOK7 — giving pyridostigmine to these patients is harmful
- Repetitive CMAP after single nerve stimulus = think AChE deficiency or slow-channel CMS (prolonged endplate current re-excites muscle fiber)
High-Yield Comparison Table
MG vs LEMS vs Botulism vs Organophosphate Poisoning
| Feature | Myasthenia Gravis | LEMS | Botulism | Organophosphate |
|---|
| NMJ defect site | Postsynaptic (AChR) | Presynaptic (VGCC) | Presynaptic (SNARE) | Synaptic (AChE) |
| Antibody / Toxin | AChR Ab, MuSK Ab, LRP4 Ab | P/Q-type VGCC Ab | Botulinum toxin | Organophosphate compound |
| Weakness pattern | Ocular → bulbar → generalized; fatigable | Proximal legs > arms; improves briefly with activity | Descending (cranial → limbs → respiratory) | Generalized (fasciculations → paralysis) |
| Reflexes | Normal | Absent (improve post-exercise) | Absent | May be absent (depolarization block) |
| Pupils | Normal | Sluggish (may be normal) | Dilated, fixed | Pinpoint (miotic) |
| Autonomic | Absent | Present (dry mouth, constipation) | Present (dry mouth, constipation, ileus) | Present (SLUDGE — excessive secretions) |
| Secretions | Normal | Dry | Dry | Wet / excessive |
| Sensory | Normal | Normal | Normal | Normal (but pain/cramping) |
| RNS (2–3 Hz) | Decrement ≥10% | Decrement (low CMAP) | Decrement (low CMAP) | Decrement (repetitive CMAPs) |
| RNS (50 Hz) or post-exercise | No increment | Increment ≥60% (AANEM current standard; historical threshold was 100%, less sensitive) | Increment (variable, often <100%) | Not typically tested |
| Cancer link | Thymoma (10–15%) | SCLC (~60%) | None | None |
| Treatment | Pyridostigmine, immunotherapy, thymectomy | 3,4-DAP, treat cancer, immunotherapy | Antitoxin, supportive ICU care | Atropine + pralidoxime |
AChR Ab+ MG vs MuSK Ab+ MG
| Feature | AChR Ab+ MG | MuSK Ab+ MG |
|---|
| Antibody class | IgG1/IgG3 (complement-fixing) | IgG4 (non-complement-fixing) |
| Predominant weakness | Ocular → generalized (limb + ocular) | Bulbar, facial, respiratory, neck |
| Facial/tongue atrophy | Rare | Common |
| Thymus | Hyperplasia or thymoma | Normal — no thymic pathology |
| Pyridostigmine | Effective | Poorly tolerated / may worsen |
| Thymectomy | Indicated | NOT indicated |
| Complement inhibitors | Effective (eculizumab, ravulizumab) | NOT effective (IgG4 → no complement activation) |
| FcRn inhibitors | Effective (efgartigimod, rozanolixizumab) | Limited data (may reduce IgG4 levels) |
| Rituximab | Second/third line | First-line IS (after steroids) |
| Crisis risk | Moderate | High (respiratory predominance) |
- Board exam pattern recognition: fatigable ptosis + diplopia = MG; proximal weakness + absent reflexes + dry mouth = LEMS; descending paralysis + dilated pupils = botulism; SLUDGE + fasciculations + miotic pupils = organophosphate
- Dry vs Wet: LEMS and botulism cause dry autonomic features (dry mouth, constipation); organophosphate causes wet features (SLUDGE)
- High-frequency RNS increment (≥60%, AANEM current standard; historical threshold was 100%) = presynaptic disorder (LEMS or botulism); no increment = postsynaptic (MG)
- The only NMJ disorder with a cancer screening protocol is LEMS — CT chest q6 months ×2 years for SCLC
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