Neuromuscular Junction Disorders

NMJ Fundamentals - Synaptic Spark

• NMJ: Specialized chemical synapse; motor neuron axon terminal connects to muscle fiber's motor end plate.
• Key Components:
  • Presynaptic Terminal: Stores acetylcholine (ACh) in vesicles; site of voltage-gated Ca2+ channels.
  • Synaptic Cleft: Contains acetylcholinesterase (AChE) for ACh breakdown.
  • Postsynaptic Membrane (Motor End Plate): Rich in nicotinic ACh receptors (nAChR); has junctional folds.
• Transmission Steps:

⭐ Voltage-gated Ca2+ channels at the presynaptic terminal are crucial for ACh release.

Myasthenia Gravis - Receptor Wreck

• Patho: Autoimmune. IgG Abs vs. postsynaptic AChRs (Acetylcholine Receptors) (80-90%) or MuSK (Muscle-Specific Kinase). ↓ACh binding at NMJ.
• Clinical: Fluctuating, fatigable weakness (worse with use/end of day, better with rest).
  • Ocular (common initial): Ptosis, diplopia.
  • Bulbar: Dysphagia, dysarthria, "nasal" voice.
  • Generalized: Proximal muscle weakness. Normal reflexes & sensation.
• Diagnosis:
  • AChR-Ab (serum, best initial). MuSK-Ab if AChR-Ab negative.
  • Electrophysiology:
    • RNS (Repetitive Nerve Stimulation): >10% decremental response at 3 Hz.
    • SFEMG (Single Fiber EMG): ↑ jitter & blocking (most sensitive).
  • Ice pack test: Improves ptosis.
  • Chest CT/MRI: For thymoma/thymic hyperplasia.

⭐ Myasthenia Gravis is strongly associated with thymic hyperplasia (70%) or thymoma (10-15%).

• Treatment:
  • Symptomatic: Pyridostigmine (AChE inhibitor).
  • Chronic Immunomodulation: Prednisolone, Azathioprine, Mycophenolate.
  • Rapid (Crisis/Severe): IVIg, Plasmapheresis.
  • Thymectomy: All thymoma patients; generalized MG in younger patients (<60-65 yrs).
• Myasthenic Crisis: Respiratory failure due to severe weakness. Improves with Edrophonium (Tensilon) test.
• Cholinergic Crisis: Due to AChE inhibitor overdose. Worsens with Edrophonium. 📌 DUMBELS (Diarrhea, Urination, Miosis, Bronchospasm/Bradycardia, Emesis, Lacrimation, Salivation) or SLUDGE-M.

Lambert-Eaton Syndrome - Calcium Blockade Blues

• Pathophysiology: Autoantibodies target presynaptic P/Q-type voltage-gated $Ca^{2+}$ channels (VGCC) → ↓ Acetylcholine (ACh) release.
• Association: Often paraneoplastic, especially Small Cell Lung Cancer (SCLC) (~50-60%).
  • 📌 LEMS: Lung cancer, Exercise helps, Motor (presynaptic), Stimulation (increment).
• Symptoms: Proximal muscle weakness (improves with brief exercise - "second wind"), hyporeflexia, autonomic dysfunction (dry mouth, constipation).
• Diagnosis:
  • Anti-VGCC antibodies.
  • Electromyography (EMG): ↓ CMAP amplitude.

  ⭐ LEMS classically shows an incremental response (facilitation >100%) on high-frequency repetitive nerve stimulation (RNS).

• Treatment: Address underlying SCLC; 3,4-diaminopyridine; immunosuppressants.

Other NMJ Disruptors - Toxic Transmissions

• Organophosphates/Carbamates: AChE inhibitors → cholinergic crisis (DUMBELS 📌). Rx: Atropine, Pralidoxime (OPs).
• Botulinum Toxin: Presynaptic block of ACh release → flaccid paralysis.

  ⭐ Botulinum toxin causes irreversible inhibition of ACh release, leading to flaccid paralysis; recovery requires sprouting of new nerve terminals.

• Tetanus Toxin: Blocks glycine/GABA release (spinal cord) → spastic paralysis.
• Aminoglycosides: ↓ Presynaptic ACh release; can worsen Myasthenia Gravis.
• Black Widow Spider Venom: Massive ACh release then depletion → cramps, pain.
• Neurotoxic Snake Venoms:
  • α-bungarotoxin: Postsynaptic AChR block.
  • β-bungarotoxin: Presynaptic ↓ ACh release.

NMJ Disorders - Compare & Contrast Clinic

High‑Yield Points - ⚡ Biggest Takeaways

• Myasthenia Gravis: Postsynaptic AChR antibodies cause fluctuating weakness (ptosis, diplopia); Tensilon test positive; thymoma association.
• LEMS: Presynaptic VGCC antibodies cause proximal weakness improving with exercise; strong SCLC link.
• Botulism: Toxin inhibits presynaptic ACh release, causing descending flaccid paralysis; infantile form via honey.
• Organophosphate Poisoning: AChE inhibition causes cholinergic crisis (DUMBBELLS); treat with atropine & pralidoxime.
• RNS: Shows decremental response in MG, incremental in LEMS.