What are the characteristics of neuromuscular junction disorders?

Characteristics of Neuromuscular Junction Disorders

Neuromuscular junction disorders are characterized by impaired signal transmission between motor neurons and muscle fibers, resulting in fluctuating and fatigable muscle weakness that affects mortality, morbidity, and quality of life.

Anatomy and Physiology of the Neuromuscular Junction

The neuromuscular junction (NMJ) is a specialized synapse between:

• Presynaptic motor neuron terminal
• 30nm synaptic cleft
• Postsynaptic muscle membrane (sarcolemma)

Normal neuromuscular transmission involves:

• Nerve action potential triggers calcium influx into nerve terminal
• Calcium influx causes acetylcholine-filled vesicles to fuse with presynaptic membrane
• Acetylcholine diffuses across synaptic cleft
• Acetylcholine binds to nicotinic receptors on sarcolemma (10,000 receptors/μm²)
• Receptor activation opens ion channels allowing Na⁺ influx and K⁺ efflux
• Membrane depolarization triggers muscle contraction
• Acetylcholinesterase in synaptic cleft hydrolyzes acetylcholine to terminate signal 1

Major Neuromuscular Junction Disorders

1. Myasthenia Gravis (MG)

• Pathophysiology: B-cell mediated autoimmune disorder with antibodies against:
  • Acetylcholine receptors (most common)
  • Muscle-specific kinase (MuSK)
  • Other postsynaptic proteins 1
• Clinical Features:
  • Fluctuating muscle weakness exacerbated by fatigue
  • Ocular symptoms (ptosis, diplopia) in 50% of patients initially
  • 50-80% of ocular-only cases progress to generalized MG within years 1
  • Bulbar, limb, and respiratory muscles may be affected
  • Potential life-threatening respiratory failure 1
• Epidemiology:
  • Incidence: 0.04-5/100,000 per year
  • Prevalence: 0.5-12.5/100,000
  • Onset typically in 3rd-4th decade (earlier in women, later in men)
  • Women affected twice as often as men 1, 2
• Diagnosis:
  • Repetitive nerve stimulation showing decremental response
  • Single-fiber EMG showing increased jitter or impulse blockade
  • Antibody testing (AChR, MuSK) 1, 3
• Associated conditions:
  • Increased risk with autoimmune thyroid disease
  • Thymoma in 10-15% of patients 1

2. Lambert-Eaton Myasthenic Syndrome (LEMS)

• Pathophysiology: Autoantibodies against presynaptic P/Q-type voltage-gated calcium channels 4, 2
• Clinical Features:
  • Late onset fatigue
  • Proximal muscle weakness (often starting in legs)
  • Autonomic symptoms (dry mouth, constipation)
  • Reflexes may be diminished or absent but can increase after exercise 5, 4
• Epidemiology:
  • Less common than MG
  • Often paraneoplastic (associated with small cell lung cancer)
  • Can also be autoimmune without cancer association 5
• Diagnosis:
  • Repetitive nerve stimulation showing incremental response after exercise
  • Antibodies against P/Q-type voltage-gated calcium channels 4, 3

3. Congenital Myasthenic Syndromes (CMS)

• Pathophysiology: Genetic mutations affecting various NMJ proteins
• Clinical Features:
  • Hypotonia and weakness from birth
  • Static or slowly progressive course
  • Facial weakness with/without ptosis
  • Generalized hypotonic posture with hyporeflexia
  • Poor muscle bulk
  • Respiratory and bulbar muscle dysfunction
  • Relatively normal cognitive development 1
• Epidemiology:
  • Estimated prevalence 1:26,000-28,000
  • RYR1 mutations most common (1:90,000) 1

Diagnostic Approaches

Electrophysiological Testing

• Repetitive Nerve Stimulation (RNS):
  • Low-frequency stimulation (3Hz) shows decremental response in MG
  • Post-exercise facilitation in LEMS (>100% increase) 1, 3
• Single-Fiber EMG (SFEMG):
  • Most sensitive test for NMJ disorders
  • Increased jitter (temporal variability between muscle fiber action potentials)
  • Impulse blocking reflects failure of neuromuscular transmission
  • Abnormal if 10% of fiber potential pairs exceed normal jitter 1, 3

Laboratory Testing

• Antibody Testing:
  • AChR antibodies (positive in 80-90% of generalized MG, 40-77% of ocular MG)
  • MuSK antibodies
  • P/Q-type voltage-gated calcium channel antibodies (LEMS)
  • Genetic testing for congenital forms 1, 4

Other Tests

• Edrophonium (Tensilon) Test: Short-acting acetylcholinesterase inhibitor causing temporary improvement in MG
• Ice Pack Test: Cooling improves ptosis in MG
• Imaging: Chest CT/MRI to evaluate for thymoma in MG or lung cancer in LEMS 1

Treatment Approaches

Myasthenia Gravis

• Symptomatic Treatment:
  • Acetylcholinesterase inhibitors (pyridostigmine) 6
• Immunosuppression:
  • Corticosteroids
  • Azathioprine, mycophenolate mofetil
  • Rituximab (especially for MuSK-positive MG)
• Thymectomy: Indicated for thymoma and in specific age-based and immune-based characteristics 1
• Acute Exacerbations:
  • Plasma exchange
  • Intravenous immunoglobulin (IVIG)

Lambert-Eaton Myasthenic Syndrome

• Symptomatic Treatment:
  • 3,4-diaminopyridine (blocks potassium channels, prolongs action potential) 5
  • Pyridostigmine (less effective than in MG) 6
• Immunosuppression: Similar to MG
• Cancer Treatment: If paraneoplastic 5

Complications and Prognosis

• Myasthenic Crisis: Life-threatening respiratory failure requiring mechanical ventilation
• Cholinergic Crisis: Excessive acetylcholinesterase inhibitor use causing weakness and cholinergic symptoms
• Respiratory Complications: Major cause of morbidity and mortality
• Thymoma: Present in 10-15% of MG patients, requires surgical removal
• Medication Sensitivity: Numerous medications can exacerbate NMJ disorders (aminoglycosides, fluoroquinolones, beta-blockers)

Special Considerations

Anesthesia and Surgery

• Increased risk of respiratory complications
• Careful perioperative management required
• Avoid medications that can worsen neuromuscular blockade 7

Pregnancy

• Variable effects on MG symptoms (improvement, worsening, or no change)
• Risk of transient neonatal MG due to transplacental antibody transfer
• Careful management of medications during pregnancy

Concomitant Autoimmune Disorders

• Higher prevalence of other autoimmune conditions (thyroid disease, rheumatoid arthritis, systemic lupus erythematosus)
• Requires coordinated multidisciplinary care

Distinguishing Features Between Major NMJ Disorders

Feature	Myasthenia Gravis	Lambert-Eaton Syndrome	Congenital Myasthenic Syndromes
Pathophysiology	Postsynaptic (AChR, MuSK)	Presynaptic (VGCC)	Various genetic defects
Distribution	Ocular, bulbar, limbs	Proximal limbs (legs first)	Variable by subtype
Reflexes	Normal or reduced	Reduced, increase after exercise	Hyporeflexia
Autonomic symptoms	Rare	Common	Variable
Response to treatment	Good with AChE inhibitors	Better with 3,4-DAP	Variable by subtype
Associated conditions	Thymoma, thyroid disease	Small cell lung cancer	Rare cardiac involvement