Disorders of the neuromuscular junction

Question 1

What are the 2 main categories of neuromuscular junction disorder?

Answer 1

Pre-synaptic
Post-synaptic

Question 2

What are some examples of pre-synaptic neuromuscular junction disorders?

Answer 2

Botulism
Lambert-Eaton myasthenia syndrome (LEMS)

Question 3

What is an example of a post-synaptic neuromuscular junction disorder?

Answer 3

Myasthenia gravis

Question 4

What bacteria causes botulism?

Answer 4

Clostridium botulinum

Question 5

Where is C. botulinum found?

Answer 5

Soil
Contaminated food
Contaminated wounds
Contaminated street heroin

Question 6

How does C. botulinum affect the neuromuscular junction?

Answer 6

It releases a potent exotoxin, which enters the presynaptic terminal to modify snare protein, which are involved in the docking of vesicles containing ACh, preventing ACh release across the synapse

Question 7

How can botulinum toxin be used medically?

Answer 7

Low dose botulinum haemaglutin complex can be administered IM to treat overactive muscles (dystonias) and also ‘botox’ for wrinkles

Question 8

Presentation of botulism

Answer 8

• Rapid onset (over hours) motor weakness, without sensory loss
• Typically ascending paralysis

Question 9

What investigations are used in botulism?

Answer 9

Detection of toxin in serum, urine, stool, vomit/gastric fluid

Question 10

Management of botulism

Answer 10

Mostly supportive - Treat respiratory failure, will improve

Antitoxin available from public health but anaphylaxis risk is common

Question 11

What is Lambert-Eaton myasthenic syndrome?

Answer 11

A paraneoplastic manifestation of small cell bronchial carcinoma in which there is defective ACh release at the neuromuscular junction

Question 12

Describe the pathophysiology of LEMS

Answer 12

Antibodies against voltage-gated Ca2+ channels in the motor neurone terminal results in reduced Ca2+ entry in response to depolarisation, causing reduced ACh release

Question 13

How does LEMS present?

Answer 13

• Proximal limb muscle weakness, sometimes with ocular/bulbar muscles, some absent tendon reflexes
• Weakness tends to improve after a few minutes of muscular contraction (exertion), and absent reflexes return

Question 14

What investigations are required in LEMS?

Answer 14

• Repetitive nerve stimulation
• Detection of underlying malignancy

Question 15

What are the pharmacological managements available in LEMS? (Surgery is also available)?

Answer 15

• Potassium channel blockers (e.g. 3,4-diaminopyridine aka amifampridine) increase the release of ACh by prolonging the action potential in the motoneurone terminal
• Immunosuppression recommended for severe cases - prednisolone and a steroid-sparing agent e.g. azathioprine

Question 16

What is myasthenia gravis?

Answer 16

Autoimmune disorder of neuromuscular junction transmission, characterized by weakness and fatiguability of proximal limb, bulbar and ocular muscles

Question 17

What is a condition that in many (75%) of patients can lead to myasthenia gravis?

Answer 17

Thymic hyperplasia/thymoma

Question 18

Describe the aetiology of myasthenia gravis?

Answer 18

Females - Most common in 3rd decade
Males - Most common in 6th-7th decades

Question 19

Describe the pathophysiology of myasthenia gravis

Answer 19

Autoantibodies agains nACh receptors in the endplate
Results in a reduction in the number of functional channels and so decreases the amplitude of the endplate potential

Question 20

How does myasthenia gravis present?

Answer 20

• Fatiguable weakness of skeletal muscle
• Most common presentation with extraocular weakness (60%), facial and bulbar weakness
• In a small number may remain only ocular
• Usually generalised
• Limb weakness typically proximal

Question 21

What investigations are required in myasthenia gravis?

Answer 21

• Serum AChR antibodies
• Single fibre EMG
• CT chest for thymoma

Question 22

What are some acute management options of myasthenia gravis?

Answer 22

• ACh inhibitor - pyridostigmine
• IV immunoglobin or plasma exchange
• Thymectomy

Question 23

What are some long term management options of myasthenia gravis?

Answer 23

• Steroids
• Steroid sparing agents - azathioprine, mycophenolate
• Emergency treatment with plasma exchange or immunoglobulin
• Avoid certain drugs - anaethesia, gentamicin