What are neuromuscular junction (NMJ) disorders?

Neuromuscular Junction (NMJ) Disorders: Definition and Classification

Neuromuscular junction disorders are autoimmune, genetic, or toxic conditions affecting the connection between motor neurons and muscle fibers, characterized by fluctuating muscle weakness that worsens with activity and improves with rest, potentially leading to life-threatening complications. 1, 2

Anatomy and Physiology of the Neuromuscular Junction

• The neuromuscular junction consists of a presynaptic motor nerve terminal, the synaptic cleft, and the postsynaptic muscle membrane 3
• When a motor neuron is activated, calcium enters the nerve terminal, triggering the release of acetylcholine-filled vesicles into the synaptic cleft 3
• Acetylcholine diffuses across the 30-nm gap to bind with nicotinic acetylcholine receptors on the muscle fiber's sarcolemma 3
• The binding opens ion channels, allowing sodium influx and potassium efflux, which depolarizes the membrane and triggers muscle contraction 3
• Acetylcholinesterase in the synaptic cleft hydrolyzes acetylcholine to terminate muscle contraction 3
• The NMJ contains approximately one-half million acetylcholine-filled vesicles and up to 10,000 acetylcholine receptors/μm² 3

Classification of NMJ Disorders

NMJ disorders are classified based on the site of neuromuscular transmission failure:

1. Presynaptic disorders:

   • Affect acetylcholine release from nerve terminals 4
   • Example: Lambert-Eaton Myasthenic Syndrome (LEMS) 4, 5

2. Synaptic disorders:

   • Affect the synaptic cleft 4
   • Example: Cholinesterase inhibitor toxicity 4

3. Postsynaptic disorders:

   • Affect acetylcholine receptors or receptor clustering 4, 5
   • Example: Myasthenia gravis 4, 5

Major NMJ Disorders

1. Myasthenia Gravis (MG)

• Most common NMJ disorder, with a prevalence of approximately 0.5 to 12.5/100,000 per year 3, 1
• B-cell mediated autoimmune disorder where antibodies attack acetylcholine receptors or proteins involved in receptor clustering 3, 1
• Types include:
  • Ocular myasthenia: affects only levator, orbicularis oculi, and extraocular muscles 3
  • Generalized myasthenia: affects larger muscle groups including bulbar, limb, and respiratory muscles 3, 1
• Clinical presentation:
  • Fluctuating weakness that worsens with activity and improves with rest 1
  • Ocular symptoms (ptosis, diplopia, variable strabismus) often appear first 1
  • May progress to difficulty chewing, swallowing, speaking, and breathing 1
• Diagnosis:
  • Repetitive nerve stimulation showing decremental response 3
  • Single fiber electromyography (SFEMG) if RNS is normal but suspicion remains high 3
  • Acetylcholine receptor antibodies present in nearly all generalized MG cases and 40-77% of ocular MG cases 3
• Treatment:
  • Acetylcholinesterase inhibitors like pyridostigmine 6
  • Thymectomy, especially if thymoma is present 3, 1
  • Immunosuppressive therapy 1

2. Lambert-Eaton Myasthenic Syndrome (LEMS)

• Presynaptic NMJ disorder caused by antibodies against voltage-gated calcium channels (VGCC) 3, 7
• Often paraneoplastic, associated with small cell lung cancer 3, 7
• Clinical features:
  • Proximal muscle weakness, predominantly at the hip girdle 3
  • Autonomic symptoms (dry mouth, constipation) 3
  • Weakness improves with repeated muscle use (facilitation) 7
• Diagnosis:
  • Repetitive nerve stimulation showing incremental response 4
  • Anti-VGCC antibodies present in >90% of cases 3
• Treatment:
  • 3,4-diaminopyridine (Firdapse) 7
  • Treatment of underlying malignancy if present 7
  • Immunosuppressive therapy 7

3. Congenital Myasthenic Syndromes (CMS)

• Genetic disorders affecting proteins of the neuromuscular junction 2, 8
• Not autoimmune-mediated 3
• Clinical features:
  • Hypotonia and weakness from birth 3
  • Static or slowly progressive course 3
• Diagnosis:
  • Genetic testing 2
  • Electrophysiological studies 2
• Treatment:
  • Depends on specific genetic defect 2
  • May include acetylcholinesterase inhibitors or 3,4-diaminopyridine 2

Diagnostic Approaches for NMJ Disorders

• Repetitive nerve stimulation (RNS): Most widely used electrodiagnostic method 4
  • Shows decremental response in postsynaptic disorders (MG) 3, 4
  • Shows incremental response in presynaptic disorders (LEMS) 4
• Single fiber electromyography (SFEMG): More sensitive than RNS 3
  • Recommended if RNS is normal but suspicion of NMJ disorder remains high 3
  • Abnormal if 10% of fiber potential pairs exceed normal jitter or have impulse blockade 3
• Antibody testing:
  • Acetylcholine receptor antibodies in MG 3
  • Muscle-specific kinase (MuSK) antibodies in seronegative MG 5
  • VGCC antibodies in LEMS 3

Clinical Implications and Management

• Early recognition and diagnosis are crucial to prevent life-threatening complications like respiratory failure 1
• Treatment should be tailored to the specific NMJ disorder 1, 5
• Monitoring for respiratory compromise is essential, particularly in generalized MG 1
• Neurologist referral is recommended for proper management 1
• Patients with NMJ disorders may have altered sensitivity to certain medications, particularly neuromuscular blocking agents used in anesthesia 3

Special Considerations

• Up-regulation of acetylcholine receptors can occur in certain conditions (motor neuron lesions, burns, muscle atrophy), increasing sensitivity to acetylcholine and decreasing sensitivity to neuromuscular blocking agents 3
• Down-regulation of acetylcholine receptors (as in MG) increases sensitivity to neuromuscular blocking agents 3
• Patients with NMJ disorders require special anesthetic considerations due to altered responses to neuromuscular blocking agents 3