NMJ Disorders

Describe the steps for motor movement from the brain to the muscle

1) Planning of movement is responsible by the premotor cortex while execution of the movement is done by 2 neurons
→ upper motor neurons in the primary motor cortex begin executing the action before synapsing with the lower motor neuron
→ lower motor neurons in the anterior/ventral horn in the spinal cord will project the axon to the target muscle fiber at the neuromuscular junction where acetylcholine is secreted

2) When acetylcholine is secreted into the synaptic cleft, acetylcholine interacts with the sarcolemma at nicotinic acetylcholine receptors
→ nicotinic receptors allow the entry of sodium accumulating end plate potentials, triggering depolarization of the muscle
→ action potential is generated and propagates to the T-tubules where calcium channels at the sarcoplasmic reticulum open and release calcium which is required for contraction

3) Acetylcholinesterase in the synaptic cleft will cleave acetylcholine and inactivate acetylcholine and prevent its accumulation
→ terminates the response

What are NMJ Disorders? What are the two kinds of NMJ disorders and the three diseases?

NMJ disorders can be either presynaptic or postsynaptic. NMJ disorders will result in less sodium entering into the muscle cell due to improper acetylcholine activity.
→ as you continuously use the muscle, the muscle fibers begin to stop firing

1) Presynaptic - disorders that are caused by impaired release of acetylcholine release
→ Lambert Eaton Myasthenic Syndrome (LEMS) - antibodies made against voltage gated calcium channels in the presynaptic terminal
→ Botulism - botulin toxin cleaves SNARE proteins

2) Postsynaptic - disorders that are caused by impaired acetylcholine signaling
→ Myasthenia Gravis - antibodies made against nicotinic acetylcholine receptors

What is the classic presentation of NMJ disorders?

NMJ disorders classically present with muscle weakness with no sensory issues

1) Patients will often present with fatigable muscle weakness, where muscles become weaker and weaker with use
→ the muscles that are most commonly affected involve a cape like pattern including the face and arms

2) Patients have ocular symptoms such as ptosis (drooping eyes) and double vision (diplopia)
→ patients can have difficulty swallowing, standing, or breathing

What would the physical exam findings be for a patient with NMJ disorders?

1) Patients often show fatigability over time, with their voice becoming more slurred and eyes drooping more over time
→ their ptosis may improve with an ice pack

2) Sensory and mental status should be alright
→ reflexes can be normal in post synaptic NMJ disorders, but can be decreased in presynaptic disorders

What is the Tensilon Test?

Tensilon is a short acting acetylcholinesterase inhibitor that should improve patients symptoms
→ if patients symptoms improve, the patient is more likely to have a NMJ disorder

What is Repetitive Nerve Stimulation

Repetitive Nerve Stimulation is a nerve conduction study where we artificially produce an action potential in a nerve of interest

1) We stimulate the nerve and observe the muscle contraction
→ when a patient is healthy, the amplitude of response will be stable overtime

2) when a patient has decrease in response with 3 Hz (low frequency) the patient has a NMJ disorder (nonspecific)
→ called a decremental response and observed in all NMJ disorders

2) when a patient has an increase in response with 50 Hz (high frequency) the patient has a presynaptic NMJ disorder
→ high frequency mimics exercise which should increase the amount of acetylcholine in the synapse

What is a Single Fiber EMG

Single Fiber EMG is a test used to assess for NMJ disorders by measuring the contraction of 2 muscle fibers innervated by the same motor axon

1) In a normal patient, the contraction of adjacent muscle fibers innervated by the same motor axon should be synchronous and standardized
→ in a patient with an NMJ disorder there is a variable relative firing time with varied time in between the time difference between contraction times

What is Myasthenia Gravis?

Myasthenia gravis is a postsynatpic disorder caused by auto-antibodies targeting the acetylcholine receptor

1) Often associated with thymoma or a rare thymus tumor
→ the mildest form is ocular myasthenia but the disease is very varied in presentation
→ fatal if respiratory failure is involved

How is Myasthenia Gravis diagnosed?

1) Myasthenia Gravis is primarily diagnosed serologically to test for the AchR antibodies in serum
→ other patients may have a CT chest scan in order to check for the presence of a thymoma

2) Rapid Nerve Stimulation have a decrement of motor responses with 3 Hz and no increment at high frequencies
→ may have jitter seen on single fiber EMG

What are the three ways myasthenia gravis is treated?

Pyridostigmine - acetylcholinesterase inhibitor
→ increases available acetylcholine

Immunosuppression
→ Azathioprine, mycophenolate, prednisone

Immunomodulation

What is Lambert Eaton Myasthenic Syndrome?

LEMS is a presynaptic NMJ disorder caused by antibodies targeting the P/Q type voltage gated calcium channels on the presynaptic terminal

1) Often caused by paraneoplastic causes or a tumor triggering an autoimmune response - is more common in women
→ patients often have a history of smoking

2) Patients have reduced reflexes and fatigued extremities
→ may have autonomic symptoms such as dry mouth and eyes

3) Reflexes are reduced and improve with repetitive muscle contraction

How is LEMS treated and diagnosed?

1) Serological testing and Neurophysiological testing
→ patients exhibit facilitation with high frequency nerve stimulation (increase in response)

2) Treated with 3,4 diaminopyridine which blocks the presynaptic voltage gated potassium channel
→ this increases the duration of the action potential, allowing for increased calcium uptake into the presynaptic terminal

What is Botulism?

Disease caused by clostridium botulinum, often presenting in patients who have eaten contaminated food

1) Spores from contaminated food or honey will germinate before targeting the SNARE components blocking the ability to release vesicles

2) Patients will often present with a descending weakness starting in their ocular/bulbar muscles then goes out distally

How is Botulism diagnosed and treated?

Botulism is diagnosed based on detection of botulinum toxin in either serum or stool sample
→ neurophysiology test with the repetitive nerve stimulation will exhibit a decrement at low frequency with facilitation at high frequency

Treat with antitoxin