Autoimmune neuromuscular junction disease with fluctuating fatigable weakness.
Also known as: MG, myasthenia gravis, Lambert-Eaton, ocular myasthenia
Overview
Autoimmune disorder caused by autoantibodies against postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction, producing fluctuating, fatigable skeletal muscle weakness. Approximately 85% have AChR antibodies; ~5-10% have anti-MuSK (muscle-specific tyrosine kinase) antibodies; ~5% are seronegative.
Epidemiology
Prevalence ~14-40 per 100,000. Bimodal incidence: women in 2nd-3rd decade and men in 6th-8th decade.
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Question 1NeurologyMedium
A 55-year-old man with small cell lung cancer develops ptosis and proximal muscle weakness that improves with repetitive use. An edrophonium (Tensilon) test is negative, and serum anti-voltage-gated calcium channel (anti-VGCC) antibodies are positive. Which of the following is the most likely diagnosis?
AAmyotrophic lateral sclerosis
BLambert-Eaton myasthenic syndrome
CAnti-AChR-positive myasthenia gravis
DParaneoplastic dermatomyositis
Reveal answer & full explanation
Correct answer: B — Lambert-Eaton myasthenic syndrome
AAmyotrophic lateral sclerosis
BLambert-Eaton myasthenic syndrome✓
CAnti-AChR-positive myasthenia gravis
DParaneoplastic dermatomyositis
Why Lambert-Eaton myasthenic syndrome is correct
Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic disorder most often associated with small cell lung cancer, caused by autoantibodies against presynaptic voltage-gated calcium channels.
Reduced acetylcholine release produces proximal weakness and hyporeflexia that characteristically IMPROVE with brief repetitive activity (post-exercise facilitation) — the opposite of myasthenia gravis.
Positive anti-VGCC antibodies and a negative edrophonium response point to a presynaptic disorder rather than a postsynaptic acetylcholine-receptor disease.
Management is treatment of the underlying malignancy plus amifampridine (3,4-diaminopyridine).
Why the others are wrong
Amyotrophic lateral sclerosis — causes mixed upper and lower motor neuron signs without an autoantibody or post-exercise facilitation (buzzword-matching weakness to a motor neuron disease).
Anti-AChR-positive myasthenia gravis — weakness WORSENS with repetition and the edrophonium test is typically positive with anti-AChR (not anti-VGCC) antibodies; chosen by anchoring on ptosis while ignoring the facilitation pattern.
Paraneoplastic dermatomyositis — proximal weakness accompanied by a heliotrope rash, Gottron papules, and elevated creatine kinase, not antibody-mediated neuromuscular-junction failure with facilitation (premature closure on paraneoplastic proximal weakness).
Question 2NeurologyEasy
A 35-year-old woman reports diplopia that worsens through the day and improves with rest, along with bilateral ptosis and fatigable proximal limb weakness. EMG shows a decremental response to repetitive nerve stimulation, and serum anti-acetylcholine receptor (anti-AChR) antibodies are positive. Which of the following is the most appropriate initial pharmacotherapy?
ARiluzole
BBotulinum antitoxin
C3,4-diaminopyridine
DPyridostigmine
Reveal answer & full explanation
Correct answer: D — Pyridostigmine
ARiluzole
BBotulinum antitoxin
C3,4-diaminopyridine
DPyridostigmine✓
Why Pyridostigmine is correct
Myasthenia gravis (MG) is an autoimmune attack on postsynaptic nicotinic acetylcholine receptors at the neuromuscular junction, producing fatigable weakness, ptosis, diplopia, a decremental EMG response, and anti-acetylcholine receptor (anti-AChR) antibodies.
Initial symptomatic therapy is pyridostigmine, an acetylcholinesterase inhibitor that increases acetylcholine available at the junction.
Chronic immunosuppression with corticosteroids +/- steroid-sparing agents (azathioprine, mycophenolate) is added for ongoing disease control, and thymectomy is considered for thymoma or generalized disease.
Why the others are wrong
Riluzole — disease-modifying therapy for amyotrophic lateral sclerosis, which causes mixed upper and lower motor neuron signs without fatigability or anti-AChR antibodies (buzzword-matching weakness to a motor neuron disease).
Botulinum antitoxin — used for botulism, which causes descending paralysis with autonomic features, not fatigable antibody-mediated weakness (confused-with a presynaptic toxin syndrome).
3,4-diaminopyridine — symptomatic therapy for Lambert-Eaton myasthenic syndrome, in which weakness improves with repetition and anti-VGCC antibodies are present (confused-with the presynaptic NMJ disorder).
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Thymic abnormalities: thymic hyperplasia (~65%, especially young women) or thymoma (~10-15%, especially older patients)
Other autoimmune conditions: autoimmune thyroid disease, rheumatoid arthritis, lupus, type 1 diabetes
Family history of autoimmunity
Pathophysiology
Anti-AChR antibodies block, cross-link (causing internalization), and complement-mediated destruction of postsynaptic AChRs at the neuromuscular junction. The result is reduced safety factor for neuromuscular transmission — repeated muscle use depletes available AChRs faster than they can be replaced, producing fatigability. MuSK antibodies disrupt clustering of AChRs. The thymus appears central to immune dysregulation in many patients.
Clinical presentation
Symptoms
Fluctuating, fatigable weakness — worse with use, better with rest
Symptoms typically worse at the end of the day
Ocular (initial in ~50%, eventually in ~85%): ptosis (often asymmetric), diplopia
NO sensory symptoms, NO autonomic symptoms (unlike GBS), pupils spared (unlike botulism)
Signs / physical exam
Ptosis worsens with sustained upward gaze
Ice pack test: 2 min ice applied over closed ptotic eye improves ptosis (cold improves NMJ transmission)
Cogan lid twitch: brief upshoot of upper lid on saccade from down to primary gaze
Fatigable diplopia, ophthalmoparesis (does not respect single nerve distribution)
Normal pupils, normal reflexes, normal sensation
Proximal limb weakness with fatigability on repeated effort
Nasal speech, soft palate weakness
Classic findings
Fatigable ptosis and diplopia worse at end of day, improving with rest.
Differential diagnosis
Lambert-Eaton myasthenic syndrome (LEMS) — Voltage-gated calcium channel antibodies, proximal leg weakness improves briefly with exercise (post-exercise facilitation), absent reflexes return after exercise, associated with small cell lung cancer (~50%)
If both negative: anti-LRP4 antibodies (low yield)
TSH, free T4 (thyroid autoimmunity)
Other autoimmune labs as clinically indicated
Imaging
CT chest with contrast (or MRI) — evaluate for thymoma in ALL patients with confirmed MG
Repetitive nerve stimulation: decremental response (>10% drop in CMAP amplitude) at low frequency
Single-fiber EMG: most sensitive — increased 'jitter' and blocking
Ice pack test, edrophonium (Tensilon) test (rarely used now due to side effects)
Diagnostic algorithm
Feature
Myasthenia Gravis
Lambert-Eaton (LEMS)
Antibody
Anti-AChR (or anti-MuSK)
Anti-VGCC (voltage-gated Ca channel)
Weakness pattern
Ocular/bulbar prominent; worsens with use
Proximal leg, improves briefly with exercise
Reflexes
Normal
Hypoactive; return after brief exercise
Autonomic symptoms
Absent
Present (dry mouth, ED, constipation)
Repetitive stimulation
Decremental at low frequency
Incremental at high frequency
Associated cancer
Thymoma (10-15%)
Small cell lung cancer (~50%)
Symptomatic Rx
Pyridostigmine
3,4-DAP (amifampridine)
Myasthenia gravis vs. Lambert-Eaton myasthenic syndrome.
Treatment
First-line
Symptomatic: pyridostigmine (acetylcholinesterase inhibitor) 30-60 mg PO every 4-6 hours, titrate to effect — improves transmission but does not modify disease
Immunosuppression: prednisone (initiate gradually — high doses can transiently worsen weakness; start low and titrate up, or hospitalize for monitoring)
Newer targeted agents: eculizumab and ravulizumab (complement inhibitors), rozanolixizumab and efgartigimod (FcRn inhibitors), zilucoplan
Thymectomy: indicated for ALL thymoma; also benefit shown in non-thymomatous AChR+ MG aged 18-50 (MGTX trial)
Second-line / adjunct
Myasthenic crisis (respiratory failure or severe bulbar weakness): ICU admission, IVIG 2 g/kg over 2-5 days OR plasma exchange, intubate if needed (FVC <20 mL/kg, NIF less negative than -30)
Pregnancy: transient neonatal MG (transplacental antibodies) in ~10-15% of newborns of MG mothers
PANCE pearls
Fatigability is the cardinal feature — symptoms worsen with use, improve with rest. Ask about end-of-day worsening.
Always image the chest for thymoma — even in seronegative MG.
MuSK MG presents with more bulbar and respiratory involvement, less ocular; treatment of choice is rituximab.
Avoid: aminoglycosides, fluoroquinolones, macrolides, magnesium-based laxatives/antacids — can precipitate crisis.
Pyridostigmine overdose mimics MG crisis (cholinergic crisis) — distinguish by edrophonium response or by SLUDGE symptoms (Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis).
Pregnancy can worsen MG in the first trimester and postpartum; magnesium for preeclampsia is CONTRAINDICATED (precipitates crisis) — use levetiracetam (or valproic acid); phenytoin can also worsen weakness and is reserved for refractory seizures.
References
MGFA 2020 — International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update (Narayanaswami et al., Neurology 2021)
MGTX Trial — Randomized Trial of Thymectomy in Myasthenia Gravis (Wolfe et al., NEJM 2016)
AAN — Evidence-based Guideline: Treatment of Myasthenic Crisis (Wendell & Levine, Neurohospitalist 2011)
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