Lambert-Eaton, Botulism & Other Neuromuscular Junction Disorders
Presynaptic failure: when acetylcholine never leaves the nerve terminal
The Presynaptic Junction
Normal transmission. A nerve impulse opens presynaptic P/Q-type voltage-gated calcium channels; calcium entry drives SNARE-mediated fusion of acetylcholine (ACh) vesicles, and ACh binds postsynaptic nicotinic receptors. Myasthenia gravis attacks the receptor side. The disorders here act before ACh is released: antibodies against calcium channels (Lambert-Eaton), toxin cleavage of SNAREs (botulism), a tick neurotoxin, or magnesium competing with calcium.
| Feature | Lambert-Eaton | Myasthenia gravis | Botulism |
|---|---|---|---|
| Target | Presynaptic P/Q calcium channels | Postsynaptic ACh receptor or MuSK | SNARE proteins |
| First muscles | Proximal legs | Eyelids, eye movements, bulbar | Cranial nerves, then descending |
| Repeated effort | Transiently stronger | Fatigues | Progressive, little fluctuation |
| Reflexes | Reduced; return after exercise | Normal | Normal or reduced |
| Autonomic | Dry mouth, constipation, impotence | Spared, pupils normal | Dilated sluggish pupils, dry mouth, ileus, retention |
| Repetitive stimulation | >100% increment after exercise or fast stimulation | Decrement at slow (3-Hz) stimulation | Increment with fast stimulation |
| Associated tumor | Small cell lung cancer | Thymoma | None |
Lambert-Eaton Myasthenic Syndrome
Mechanism. IgG against P/Q-type calcium channels reduces calcium entry, so each impulse releases fewer ACh quanta. About half of cases are paraneoplastic, nearly always with small cell lung cancer (SCLC); the rest are autoimmune, often in younger nonsmokers with other autoimmune disease.
Clinical picture. Proximal leg weakness makes stairs and chairs hard. Strength briefly improves with repeated effort, and depressed reflexes reappear after 10 seconds of maximal contraction (post-exercise facilitation). Dry mouth, constipation, erectile dysfunction and orthostasis are common, whereas ptosis and diplopia are mild and respiratory failure is rare.
Diagnosis. Nerve conduction shows low baseline CMAP amplitudes that decrement at 3-Hz stimulation but rise by more than 100% after 10 seconds of maximal exercise or with 20–50 Hz stimulation. P/Q-type VGCC antibodies are present in about 85–90%.
SCLC can surface up to about 2 years after LEMS is diagnosed: image the chest with CT (FDG-PET if negative) at diagnosis and repeat screening every 3–6 months for about 2 years, especially in smokers.
Treatment. Treating SCLC often improves LEMS. Amifampridine (3,4-diaminopyridine) blocks presynaptic potassium channels, prolonging depolarization so more ACh is released; it causes perioral and fingertip paresthesias and, at high doses, seizures, so it is avoided with a seizure history. Pyridostigmine adds modest benefit, and IVIG or immunosuppression (prednisone, azathioprine) is used for autoimmune or refractory disease.
Botulism
Presentation. Botulinum toxin cleaves SNARE proteins and blocks ACh release at neuromuscular and cholinergic autonomic synapses, causing a symmetric descending paralysis: diplopia, ptosis, dysarthria and dysphagia, often with dilated, poorly reactive pupils, then neck and arm weakness, respiratory failure and finally leg weakness. Patients are alert and afebrile with normal sensation, plus dry mouth, constipation and urinary retention.
Forms. Foodborne botulism comes from preformed toxin in home-canned low-acid vegetables or fermented fish, with nausea, vomiting or diarrhea typically 12–36 hours after ingestion, often in clusters. Wound botulism follows spore germination in contaminated wounds, classically subcutaneous black-tar heroin injection, with no GI prodrome. Infant botulism, the most common US form, follows swallowed spores (honey, soil, construction dust) that colonize the infant gut and make toxin in situ; infants under 1 year, usually under 6 months, develop constipation, then poor feeding, weak cry, ptosis, sluggish pupils, lost head control and hypotonia. Honey is avoided before age 1.
- Treat on clinical suspiciontoxin assays of serum, stool or food take days; notify public health, since one case may mean an outbreak
- Give antitoxin nowheptavalent equine antitoxin for adults and older children; human botulism immune globulin (BabyBIG) for infants — it halts progression but cannot reverse established paralysis
- Protect the airwayICU care with serial forced vital capacity and negative inspiratory force; intubate early as they fall
- Treat the sourcedebride wounds and give penicillin for wound botulism; no antibiotics in infant botulism and never aminoglycosides
Recovery requires sprouting of new nerve terminals, so ventilation may be needed for weeks to months.
Other Causes and Drug Triggers
Tick paralysis. A salivary neurotoxin from an engorged tick (Dermacentor in North America) impairs ACh release. Over hours to days a child, often a girl whose long hair hides the tick, develops ataxia and ascending flaccid paralysis with areflexia, no fever and normal CSF — a Guillain-Barré mimic. Removing the tick brings improvement within hours to a day or two, so search the scalp, ears and skin folds.
Hypermagnesemia. Magnesium competes with calcium at the presynaptic terminal. Toxicity is usually iatrogenic: magnesium sulfate for preeclampsia, or magnesium-containing laxatives and antacids in kidney failure. Loss of patellar reflexes comes first, then weakness, respiratory depression, hypotension, bradycardia and cardiac arrest. Stop magnesium and give IV calcium gluconate.
Drugs that unmask myasthenia. Aminoglycosides, fluoroquinolones, macrolides (such as azithromycin), β-blockers, IV magnesium, neuromuscular blockers and procainamide can unmask junction weakness or precipitate myasthenic crisis, so alternatives are chosen in MG or LEMS. Immune checkpoint inhibitors can trigger new myasthenia, often with myositis (high CK) and myocarditis (troponin, ECG changes).