Neuromuscular Junction L3

What does NMJ stand for?

neuromuscular junction

What does NM stand for?

neuromuscular

Ach stands for:

acetylcholine

AchR stands for:

acetylcholine receptor

MG stands for:

myasthenia gravis

What is the physiologic chain of command from brain to muscle contraction?

brain

motor neuron pathway

neuromuscular junction - transmission of signal from electrical to chemical

muscle fiber

contraction

If there was a pathology associated with a muscle fiber, how would it likely present?

It wouldn’t improve with short periods of rest, but rather would remain weak until healed

The nerve terminal that innervates a muscle fiber is called:

motor unit

The NMJ is the point between:

the nerve terminal and muscle fiber

T/F: NMJ is a signal transducer.

true

What neurotransmitter plays a major role in the electrical conduction across the synaptic cleft?

acetylcholine - chemical NT

Choline comes from the _____.

GI tract

AcetylCoA comes from:

Kreb’s Cycle in mitochondria

“donates” acetyl to make choline acetyltransferase, which becomes acetylcholine

The vesicle carrying Ach is made from what?

proteins within neuron; comes from the cell body

T/F: nicotinic receptors are associated with somatic nervous system.

true

innervate SKM

T/F: muscarinic receptors are found in SKM and are associated with the autonomic nervous system.

False. they are found in smooth muscle and are associated with the ANS

What is responsible for hydrolyzing Ach that has been released by the nerve terminal to prevent the repeated binding of Ach and for “recycling”?

acetylcholinesterase

Which hypersensitivity is IgE mediated?

Type I

Which hypersensitivity involves cytotoxic antibodies?

Type II

Which hypersensitivity involves antigen/antibody ~ complex deposit?

Type III

Which hypersensitivity is T Cell mediated and is known as a delayed hypersensitivity?

Type IV

What is the most common NMJ disorder?

myasthenia gravis

T/F: myasthenia gravis affects skeletal muscle as that is its main target.

False. MG does affect skeletal muscle, but it is not the main target of this autoimmune disease

Is MG an Autoimmune disorder?

Yes

Which NMJ disorder presents with bimodal distribution and why?

MG

unknown why

What is the bimodal distribution of MG?

females 20-30 y

males 60-70 y

Which NMJ disorder involves auto-Abs against the nicotinic acetylcholine receptor (AchR) on the postsynaptic membrane?

MG

MG is an ____________ disorder that involves _________ against the _______________ receptor on the _________ membrane. This leads to impaired ____________.

autoimmune

auto-antibodies

nicotinic acetylcholine receptor

postsynaptic

NM transmission

How does MG lead to impaired NM transmission?

It is an autoimmune disorder that involves the auto-Abs against the nicotinic acetylcholine receptor on the postsynaptic membrane

What kind of hypersensitivity is MG?

Type II hypersensitivity reaction - cytotoxic antibodies

MG is associated with __________ in 10-15% of patients.

thymoma

Thymoma is present in _____% of MG patients?

10-15

In MG pathophysiology, _____ bind to _______ AchR on muscle cell membrane.

auto-Abs

nicotinic

Because the nicotinic receptors are bound to the auto-abs, they cannot respond to what? What is this called?

Ach

competitive inhibition

When AchR cannot accept Ach, what takes place?

AchR will prematurely internalize so it is no longer on the cell membrane

it will decay

this leads to the activation of the complement system

MAC complex leads to cell lysis

What two ways does MG cause muscle weakness?

By blockade of Ach receptors

By receptor internalization/degradation

Some patients produce another form of antibody that attacks the protein inside the muscle cell. What is this antibody called?

muscle specific receptor tyrosine kinase antibodies MuSk

What do MuSk antibodies do?

attack proteins inside the cell

What is the most common MG presentation?

extra-ocular muscle involvement: ptosis - droopy eyelids; diplopia - blurry or double vision

What is another presentation of MG?

Progressive SKM weakness that worsens with activity, but improves with rest.

How are eye muscles affected by MG?

through ptosis and diplopia

How are the bulbar muscles (muscles innervated by CN 9-12; part of corticobulbar tract) affected by MG?

dysarthria - difficulty speaking due to impaired muscles

difficulty chewing/swallowing

dyspnea - shortness of breath

How are proximal muscles affected by MG?

difficulty standing up from a chair

difficulty climbing stairs

difficulty brushing hair

~ difficulty and weakness increases with repetitive movements

How are respiratory muscles affected by MG?

Dyspnea

respiratory failure

What is a myasthenia crisis?

An acute, life-threatening exacerbation

What triggers a myasthenia crisis?

stressors such as an infection, pregnancy, surgery/anesthesia, medications, IV contrast

What does a myasthenia crisis lead to?

Acute respiratory failure, when muscles literally cannot work to take a breath

What are the signs/symptoms of myasthenia crisis?

acute muscle weakness systemically

dyspnea

ANS responses: sweating, agitation, tachycardia, urinary and fecal urgency

disorientation

drowsiness

What treatment methods are used for myasthenia crisis?

Early intubation

high dose of prednisolone to aid in decreasing immune response

IVIG therapy - IG = immunoglobulin Abs ~ competitive inhibition of auto-antibody

What are the medications that must be avoided in MG patients to prevent myasthenia crisis?

• Muscle relaxants — especially succinylcholine

• Fluoroquinolones

• Macrolides

• Aminoglycosides

T/F: The thymus is slightly larger in adult patients than pediatric patients.

False. The thymus should be much smaller on adult patients than pediatric patients. On radiograph, it should not be visible for adults.

Where is the thymus in the thoracic cavity in relation to the heart?

Anterior mediastinum

What percentage of patients with MG will develop thymoma?

10-15%

T/F: Patients with MG should only undergo screening for thymoma if symptoms are present.

False. all patients should be screened routinely for thymoma

What is the function of the thymus?

to produce T Cells. Production is at a higher rate in pediatric patients than in adults

Define paraneoplastic syndrome.

A group of symptoms that may develop when substances released by some cancer cells disrupt the normal function of surrounding cells and tissue.

Thymoma + MG become a ________ syndrome.

paraneoplastic

T/F: It is uncommon to have a second autoimmune disease alongside of the first diagnosed autoimmune disorder.

False. It is common for an autoimmune disorder to occur alongside another autoimmune disorder.

What is the initial lab diagnostic test for MG?

anti-AchR antibodies

For the lab diagnostic test for MG, what is the second test to complete if the anti-AchR antibody test is negative?

anti-MuSK antibodies

What is another important step in diagnosing MG?

Ruling out other autoimmune disorders

Why would a chest CT be recommended during diagnostic testing for MG?

To check for thymoma

What other thymus-related conditions should be ruled out with MG?

Hyerthyroidism

hypothyroidism

How often should MG patients be screened for thymoma?

every few years

Which test can be completed in clinic that helps inhibit the enzyme that degrades Ach in the synaptic cleft to allow Ach levels to remain and increase the chances of receptor binding and muscle contraction?

Edrophonium test

What is the edrophonium test?

A rapid-acting, short duration acetylcholinesterase inhibitor

Why is the edrophonium test beneficial?

It increases Ach concentration in the NMJ

promotes binding to AchR

improves NM transmission

Leads to muscle contraction

What is a clinical test that can be used to identify if patient is likely to have MG?

Milkmaid handshake

ask the patient to shake your hand

if the pattern of grip strength is weak —> strong —> weak —> strong they may have MG

T/F: Treatment of MG is often uneffective.

False. Treatment of MG is often effective

What is the first line of treatment for MG?

Cholinesterase inhibitors

First line agent is PYRIDOSTIGMINE titrated to symptom relief

~ similar to edrophonium but longer lasting

What is another form of treatment for MG?

Immunosuppression:

• Glucocorticosteroids - given when the patient has immune reaction flare-ups but not for long term use

• indicated for inadequate symptom control of or intolerance to pyridostigmine

What is another form of treatment for MG?

Thymectomy:

• most patients with thymoma and some without if symptoms are not improving with other forms of treatment

What kind of disorder is Lambert-Eaton Syndrome (LEMS)?

a rare NMJ disorder

How does LEMS differ from MG?

It is more rare

patients experience proximal muscle weakness and autonomic dysfunction

What paraneoplastic syndrome do 2/3 of patients with LEMS have?

small cell lung carcinoma

How many LEMS patients are also diagnosed with small cell lung carcinoma?

2/3

Where is the area of concern in the NMJ with LEMS?

After the AP is reached, anti-voltage gated calcium channel antibodies lead to decreased calcium influx, which leads to decreased vesicle fusion and impaired Ach release

Patients with LEMS present with ______ muscle weakness that ______ with repetitive or ongoing use.

proximal

improves

Why would patients with LEMS present with proximal muscle weakness that improves with repetitive or ongoing use?

The body needs time for the signal to reach the muscle

with repetitive use, the muscle understands that there is an ongoing command and that Ach is present.

Need enough/increased concentration of Calcium to lead to presynaptic vesicle fusion

Which NMJ disorder presents with proximal muscle weakness that improves with repetitive or ongoing use?

Lambert-Eaton Syndrome

LEMS presentation includes with Autonomic Sxs?

dry mouth

constipation

erectile/ejaculatory dysfunction

orthostatic dysregulation ~ dizziness

How is LEMS diagnosed?

testing for specific auto-Abs

physical exam reveals increased hand grip strength ~ hand strength increases with longer duration of handshake

How is LEMS treated?

Treat the underlying malignancy - small cell lung cancer

Amifampridrine - blocks presynaptic K+ channels, eventually increases presynaptic calcium concentrations

What is amifampridrine used to treat?

LEMS

blocks presynaptic K+ channels, eventually increases the presynaptic calcium concentrations