Disorders of NMJ

Question 1

What are 3 proposed mechanisms of the pathophysiology of myasthenia gravis?

What type of structural changes would you see post-synaptic membrane?

Answer 1

1) Direct blockade of Ach receptors by auto-antibodies.
2) Accelerated of Ach receptor internalization and degradation.
3) Complemented-mediated lysis (via MAC complex) of post-synaptic membrane, resulting in loss of normal convoluted structure.

Question 2

Common clinical features of myasthenia gravis?

Answer 2

Eyes: ptosis with prolonged upward gaze, diploplia
Facial: “snarling” smile
Thymus: Associated with thymic tumor or hyperplasia–loss of self-tolerance that can lead to autoimmunity.

Weakness with increased activity that improves with rest.

Question 3

Features of myasthenia gravis crisis?

Answer 3

1) Respiratory muscle failure due to inspiratory and expiratory muscle weakness
2) Oropharyngeal weakness/Upper airway compromise leading to problems with swallowing/secretion clearance –> increases risk of aspiration

Question 4

What are some different ways to diagnose myasthenia gravis?

Answer 4

1) Ice test - in setting of ptosis, ice can decrease Ach-ase activity, thereby improving ptosis.
2) Tensilon (Edrophonium Chloride) test - short acting Ach-ase inhibitor
3) Serological test - autoantibody against Ach receptor
4) Electrodiagnostic test - repetitive nerve stimulation leads to decrease in response

Question 5

Management for myasthenia gravis.

Answer 5

1) Pyridostigmine bromide (cholinesterase inhibitor) for symptomatic treatment; risk for cholinergic crisis
2) Short term management with PLEX/IVIG such as for intervention for MG crisis
3) Long term management with prednisone/steroids
4) Immunosuppressants: Azathioprine, mycophenolate, cyclosporine, rituximab
5) Thymectomy –> shown to improve clinical status
6) Eculizumab (adjunctive therapy)–> blocks formation of complement-mediated MAC complex

Question 6

LEMS is associated with paraneoplastic syndrome of what tumor?

Answer 6

Small cell lung cancer

Question 7

Pathogenesis for LEMS/Lambert-Eaton Myasthenic Syndrome

Answer 7

Antibodies against pre-synaptic Ca2+ channels, thereby inhibiting Ca2+ influx and subsequent Ach release to NMJ –> muscle weakness that IMPROVES with continuous muscle activation/contraction

Get chest CT for SCLC, PET scan if negative CT

Question 8

LEMS clinical features

Answer 8

Gradual onset proximal weakness

Areflexia

Autonomic dysfunction - dry mouth, constipation, dry eyes, etc.

Question 9

Pathophysiology of botulism

Answer 9

Gram positive bacilli toxin that inhibits SNARE proteins that normally facilitate vesicular fusion to release Ach –> subacute FLACCID weakness

• Foodborne botulism: ingestion of preformed toxin
• Intestinal/infant botulism: ingestion of bacterial spores that germinate and produce toxin
• Wound botulism: spores germinate in anaerobic environment of deep wounds