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Myasthenia Gravis Flashcards

1
Q

What are some of the physiological effects of the sympathetic nervous system activation?

A

Sympathetic nervous system is known to initiate the ‘flight or fight’ response.

Physiological effects of stimulation:
Tachycardia
Vasoconstriction
Bronchial relaxation
Reduced gut motility (Sphincter contraction)
Pupil dilation
Inhibition of glandular secretion (except epinephrine and norepinephrine)

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2
Q

What are some of the physiological effects of the parasympathetic nervous system activation?

A

Parasympathetic nervous system is known to initiate the ‘rest and digest’ response.

Physiological effects of stimulation:
Bradycardia (reduced heart rate)
Vasodilation
Bronchial constriction
Increased gut motility (Sphincter relaxation)
Bladder contraction (Sphincter relaxation)
Pupil constriction
Stimulates glandular secretion

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3
Q

What type of disease is myasthenia gravis and what does it affect?

A

Myasthenia gravis is a chronic autoimmune disorder of the postsynaptic membrane at the neuromuscular junction in skeletal muscle.

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4
Q

How is Myasthenia Gravis characterised?

A

It is characterised by generalised skeletal muscle weakness that improves on rest and is aggravated with exercise.

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5
Q

What is the incidence of Myasthenia Gravis cases a year worldwide?

A

5.3 per 1,000,000 a year are diagnosed with the condition.

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6
Q

What is the worldwide vs the UK prevalence of Myasthenia Gravis each year?

A

77.7 per 1,000,000 worldwide whereas
15 per 100,000 people in the UK

This would work out as:
150 per 1,000,000 in the UK

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7
Q

Is the prevalence of Myasthenia Gravis cases likely to be an over or underestimate?

A

Most likely an under estimate due to the difficulty in diagnosing in older patients due to fluctuations in symptoms and similarities of symptoms with other conditions.

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8
Q

What is the mortality of Myasthenia Gravis?

A

0.1-0.9 per 1,000,000 a year

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9
Q

Is there a known cause of Myasthenia Gravis (MG)?

A

No there is not a known cause of the condition.

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10
Q

How does the most prevalent age of onset differ between men and women for MG?

A

In females this peaks between 20-30 years and then elderly

For males this peaks between 60-80 years

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11
Q

What are the ocular symptoms associated with MG?*

A

Ptosis (dropping of the eyelid)
Diptopia (double vision)
Restricted eye movements

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12
Q

Aside from the ocular symptoms, what are some of the key signs and symptoms associated with MG?

A

Lack of facial expression
Slurred speech
Difficulty chewing
Dysphagia (difficulty swallowing)
Weakness in arms, legs and neck

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13
Q

What times of day do symptoms of MG tend to be more apparent?

A

Normally later in the day (after a period of activity)

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14
Q

What additional symptoms would you expect to see in Myasthenic crisis?

A

Shortness of breath - Difficulty/Laboured breathing (diaphragm is skeletal muscle)

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15
Q

State the 5 tests used in the diagnosis of MG.

A

Ice test
Blood test
Neurophysiology tests
Edrophonium test
CAT scan

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16
Q

How is the Ice test used for diagnosing MG?

A

Typically a patient with MG you would expect to see an improvement in skeletal muscle strength after applying ice.

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17
Q

Explain the procedure of the Ice test and what is considered to be a positive result.

A

Ice pack test can be done by taking baseline eyelid measurement.
Ice pack is then applied for 2–5 min and the eyelid is re-measured after that. If there is improvement of 2 mm or more, it’s considered a positive test.

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18
Q

What auto-antibodies is a blood test expected to detect, if positive for MG?

A

Most commonly:
Acetylcholine receptor (AchR) antibodies Binding Blocking Modulating

But the patient may also have:
Muscle specific kinase (MuSK) antibodies

Lipoprotein receptor related antibody 4 (LRP4)

Titin (anti-striated muscle) antibodies

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19
Q

What does the Neurophysiology test entail?

A

An electromyogram is used which measures the muscle compound action potential in response to repeated stimulation.
If a patient is positive for Myasthenia Gravis you would expect there to be an decrease in muscle response in comparison to a patient without MG.

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20
Q

When is the Edrophonium test used?

A

In diagnosing MG
For differentiating a Myasthenic Crisis to a Cholinergic crisis in a patient with MG.

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21
Q

How does the Edrophonium test work?

A

Edrophonium is a drug that acts as reversible (short acting) cholinesterase inhibitor. Hence it works by preventing the breakdown of acetylcholine by reversibly inhibiting the enzyme Acetylcholinesterase.
By using this drug in patients with MG you would expect them to experience an improvement in their symptoms (for example ptosis is reversed).

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22
Q

What is a CAT scan used to rule out?

A

It is used to exclude a Thymoma which is causing a patients symptoms.

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23
Q

Does MG reduce life expectancy?

A

For most patients with MG they proceed to live normal lives by pharmacological management and lifestyle adjustments.
Most live without a reduced life expectancy but there is an attached mortality with the condition.

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24
Q

What are the first symptoms of MG and when do they tend to progress?

A

Symptoms usually begins ocular, 80% of patients with MG will progress as the muscle weakness spreads to other areas.
There is no definitive time frame however, this progression could be within a matter of weeks or after a number of years.

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25
Q

What percentage of patients with MG experience a MG crisis?

A

20%

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26
Q

What happens to a patient during a Myasthenic Crisis?

A

Myasthenic crisis occurs when a patient with MG has increasing weakness in their muscles which regulate breathing (skeletal muscles of the diaphragm) to the point where mechanical ventilation is required.

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27
Q

What do the drugs used in MG work to do?

A

Particularly the first line drugs used in Myasthenia Gravis (acetylcholinesterases inhibitors) are used to enhance the neuromuscular transmission, improving muscle contractility hence muscle strength.

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28
Q

What is the first line treatment used when a patient is first diagnosed with MG?

A

As a patients first presents with ocular symptoms, when a patient suffers with ocular symptoms alone - Anticholinesterases are used (Pyridostigmine and Neostigmine)

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29
Q

When a patient experiences symptoms outside of just ocular symptoms what pharmacological therapy is used?

A

A anticholinesterase in combination with an immunosuppressant (corticosteroids) for generalised MG symptoms.

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30
Q

When is Azathioprine used in the treatment of MG?

A

Used in adjunct when corticosteroids are used in order to reduce their dose (side effects of corticosteroid therapy).

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31
Q

What is used in the management of Myasthenic crisis?

A

A patient is in Myasthenic crisis is suffering from respiratory failure to some extent.
Depending on the extent on the failure either,
Non-invasive Bilevel positive airway pressure (BiPap) or
Full intubation and ventilation

Patient may receive Plasmapheresis or infusion of intravenous immunoglobulin to induce remission.

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32
Q

Aside from use in inducing remission in a Myasthenic Crisis, when else are plasmapheresis or infusion of intravenous immunoglobulin used in MG management?

A

Before a thymectomy

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33
Q

What is a key counselling point regarding the dosage of acetylcholinesterase inhibitors?

A

When excessive doses of anticholinesterases are used they can cause impaired neuromuscular transmission and precipitate a cholinergic crisis by a depolarisation block.
It is crucial to be able to differentiate between a cholinergic crisis (caused by over-medicating) and a myasthenic crisis (uncontrolled MG) to ensure the correct management.

34
Q

What are the key differences between the cause of Myasthenic Crisis and a Cholinergic crisis?

A

Myasthenic crisis occurs when there is little to no acetylcholine acting at the neuromuscular junction which results in severe muscle loss and potentially respiratory failure.
This is caused by under medication of acetylcholinesterase inhibitors or acute exacerbation (stress on the body, respiratory infection).

Cholinergic crisis occurs when there is an overstimulation of acetylcholine at the neuromuscular junction and autonomic ganglion due to excessive amounts resulting in an overdrive in the cholinergic response leading to severe muscle weakness and respiratory failure. Caused by receiving too high a dose of acetylcholinesterase inhibitor, there is a complete inhibition of acetylcholine breakdown.

35
Q

What are some of the symptoms of a Myasthenic crisis?

A

Main symptoms:
Severe muscle weakness
Respiratory failure

Increased blood pressure
Increase in heart rate
Dilated pupils
Can’t swallow or speak
At risk of aspiration
Bladder and bowel incontinence

36
Q

What are some of the symptoms of a Cholinergic crisis?

A

Similar to parasympathetic overdrive:

GI problems: vomiting, diarrhoea, abdominal cramps
Pupil constriction
Increase in salivary and sweat secretion
Increased respiratory secretion
Muscle fasciculation (twitching) can lead to paralysis
Decrease in heart rate and blood pressure

37
Q

Describe the test used to differentiate between Myasthenic crisis and Cholinergic crisis.

A

Tensilon test:

Edrophonium (an acetylcholinesterase inhibitor) is administered to the patient.
In a patient that is in Myasthenic crisis there will be an improvement in their symptoms as this drug will prevent the breakdown by acetylcholine leading to an increase in concentration able to stimulate at the neuromuscular junction leading to an improvement in symptoms.
Whereas in a cholinergic crisis which is caused by excess acetylcholine when a drug is given which inhibits the breakdown of this excess acetylcholine there is no improvement in their symptoms and they may worsen as there will be an increase in acetylcholine.

38
Q

Which drugs are used to treat a Cholinergic crisis?

A

Atropine and hold the patient’s acetylcholinesterase inhibitor medication.

39
Q

Which drugs are used to treat a Myasthenic crisis?

A

Anticholinesterase medication/ acetylcholinesterase inhibitor medication

40
Q

What are the key points to consider in the management of MG?

A
  • Work with patients in order to be able to identify possible triggers for exacerbation of symptoms and strategies how to avoid them.
  • Initiate appropriate pharmacological treatment that helps to reduce symptoms and provide minimal side effects.
  • Introduction (if appropriate) of immunosuppressant drugs which treats the underlying immune dysfunction.

-Use of immunomodulatory therapies (plasma exchange) to induce remission during a Myasthenic crisis.

41
Q

What are some of the triggers known to exacerbate symptoms of MG?

A

Infection
Stress
Trauma
Thyroid dysfunction
Withdrawal of acetylcholinesterase inhibitors
Rapid introduction or increase of corticosteroids
Anaemia
Electrolyte imbalance
Medicines

42
Q

What are some of the ongoing monitoring a patient with MG may receive?*

A

Effects of antibiotics
Effects of certain factors on thyroid function
Monitoring for electrolyte imbalance in drugs known to cause electrolyte imbalance
Drugs prescribed to treat any additional co-morbidities a patient may have should be assessed for their risk of having an adverse effect on MG control

43
Q

How could the risk of infection be reduced in a patient with MG?

A

Whilst a patient with MG isn’t necessarily at an increased risk of infection, if they do catch an infection they are likely to have an exacerbation of their symptoms but also some of the drugs they may be introduced on can increase the risk of infection.

Annual flu vaccine
Pneumococcal vaccine
Avoid probiotics
Patients should provide an up to date immunisation record to identify any missed vaccines so that they can be administered before start immunosuppressant therapy
Avoid live vaccines (such as MMR) whilst taking immunosuppressant therapy
Contact clinician if you come into contact with Varicella Zooster virus (chickenpox) and you haven’t had it before

44
Q

Which types of drugs have the greatest impact in the control of MG management (in terms of their mechanism)?

A

Drugs that interfere with the neuromuscular transmission

Drugs that increase muscle weakness

45
Q

The known trigger meds that fall into either category are they completely contra-indicated in MG patients?

A

Ideally yes but if there is no alternative they must be monitored and titrated under close supervision.

46
Q

What are some drugs that interfere with the neuromuscular junction?

A

Phenytoin, Carbamazepine

Aminoglycosides, Colistimethate, Clindamycin, Macrolides, Telithromycin

Antimuscarinic antagonists

Procainamide and Lidocaine

Lithium and Chlorpromazine

Hydroxychloroquine

47
Q

What are the two acetylcholinesterase inhibitors available on the market?

A

Pyridostigmine
Neostigmine

48
Q

What are some drugs that cause muscle weakness?

A

Magnesium (causing hypermagnesia)
Benzodiazepines
Beta blockers (smooth muscle relaxation)*
Diuretics (alter kidney function)*
Verapamil
Statins

49
Q

Are the acetylcholinesterase inhibitors effective in every patient?

A

The response to acetylcholinesterase inhibitors is variable across patients and differs in which symptoms it relieves.

50
Q

What is the starting dose for acetylcholinesterase inhibitors?

A

15mg four times a day with food

51
Q

What strength dose acetylcholinesterase inhibitors come in?

A

They come in 60mg tablets that can be halved and quartered depending on the dose.

52
Q

What is the maintenance dose for acetylcholinesterase inhibitors?

A

Usually 60mg four to six times a day

53
Q

Why does the dose of acetylcholinesterase inhibitors have to be titrated?

A

To monitor the patient closely for therapeutic response but also for the potential of adverse reactions.

54
Q

What are some of the adverse effects associated with nicotinic receptor stimulation?

A

Muscle and abdominal cramps

55
Q

What are some of the adverse effects associated with muscarinic receptor stimulation?

A

Gut hypermobility (cramps and diarrhoea)
All the parasympathetic mediated responses:
Increased sweating and salivation
Lacrimination
Hypotension
Bradycardia
Miosis
Urinary incontinence
Increased bronchial secretions
Tachypneoa

56
Q

Is inducing a cholinergic crisis associated with overdose of acetylcholinesterases common?

A

Not it is rare with doses in the therapeutic range.

57
Q

How is it suggested to manage the side effects of acetylcholinesterases?

A

Take with food to reduce GI side effects
Co-prescribe with oral anti-cholinergic drugs (which have no nicotinic effects) so don’t reduce muscule weakness but can reduce some of the other side effects.
Examples include:
-Glycopyroolate
-Propantheline

Loperamide can be prescribed for diarrhoea

58
Q

What are some of the pharmaceutical care issues associated with MG management?

A

Identifying drugs that can exacerbate MG

Reviewing these drugs regularly- do they have a specific indication or is there a drug that can be used instead

If used patient must be closely monitored for MG deterioration

Managing deteriorations

Patients with MG might be unable to swallow- is there another formulation that can be used instead

If there are MG exacerbations or therapy is failing to control their condition then treatment step up will be required.

59
Q

What is responsible for impaired transmission at the NMJ in MG?

A

In Myasthenia Gravis which is an auto-immune disease, autoantibodies are made which antagonise the nicotinic acetylcholine receptors which prevents acetylcholine binding and hence inducing signal transmission to the muscle from the neuron.

60
Q

Explain what usually occurs at the NMJ for muscle contraction?

A

Firstly there is an action potential which propagates signals along the axon until the synapse is reached. Depolarisation causing the opening of the voltage gated calcium ion channels causing the influx of calcium ions into the synaptic terminal resulting in the exocytosis of acetylcholine which diffuses across the synaptic cleft. Acetylcholine acts on acetylcholine nicotinic receptors in the junction folds of the muscle membrane. The presence of acetylcholine then opens the ligand gated ion channels causing sodium ions to rush into the cell which produces a depolarisation in the cell called an excitatory post-synaptic potential (end plate potential). Action potential leads to contraction of the muscle.

61
Q

Which muscles are most affected in MG and why?

A

Use-dependent muscle are most affected so for example the eyelids, muscles in the face.

62
Q

Explain the rationale for using acetylcholinesterase inhibitors in treatment for MG.

A

Once acetylcholine has acted at the nicotinic acetylcholine receptors at the junctional folds of the muscle membrane, the effect is short lived as acetylcholinesterase is the enzyme responsible for the breakdown of acetylcholine preventing constant stimulation of the receptors. However in MG where auto-antibodies antagonise the nicotinic receptors causing impaired transmission, you would want to prolong the action of any acetylcholine that is able to bind hence inhibiting the enzyme responsible for degrading it- acetylcholine stays in the synapse for longer and its activity is enhanced and there is improved muscle contraction .

63
Q

Explain the synthesis and storage of acetylcholine within the synaptic membrane.

A

Acetylcholine as in the name is produced by the combination of an acetyl group and choline.
Choline exists extracellularly and is uptake by a Choline/Na+ symporter An acetyl group is added to choline by choline acetyltransferase enzyme with the acetyl group supplied for acetyl coA (product of glycolysis).
Acetlycholine is uptaken for storage in vesicles by an antiporter mechanism with Hydrogen (converts ATP for ADP in this mechanism).
Acetylcholine remains in vesicles until there is an influx of calcium in the neuron as a result of an action potential.

64
Q

What does acetylcholinesterase do?

A

Terminates the activity of acetylcholine in the synaptic cleft

65
Q

Explain the pharmacology of acetylcholine esterase inhibitors at the somatic efferent nervous system.

A

Acetylcholine esterase inhibitors, inhibit the enzyme Acetylcholine esterase from breaking down acetylcholine and therefore augment and prolong the activity of acetylcholine at the neuromuscular junction. In application to MG where the signal transmission is impaired due to the presence of autoantibodies antagonising nicotinic receptors this enhances and prolongs activity of acetylcholine, increasing the twitch tension so for a given input of acetylcholine there is a greater contraction of skeletal muscle.

66
Q

What happens to the degradation products of acetylcholine?

A

Choline is recycled again and uptaken to be used again in combination with an acetyl group.

67
Q

Which Acetylcholine esterase inhibitors are available and what are their indications?

A

Neostigmine and Pyridostigmine - MG
Malathion- Headlice
Donepezil - Alzheimer’s

68
Q

State the two different types of cholinesterase.

A

Acetylcholinesterase
Butyryl cholinesterase

69
Q

What are the key differences between Acetylcholinesterase and Butyryl cholinesterase?

A

AChe is membrane bound in the synaptic cleft or is in a soluble form in the pre-synaptic terminal or cerebrospinal fluid (anywhere with ACh synapse) . Whereas BuChe is found in the plasma, liver and in the skin.

AChe is specific for ACh whereas BuChe has a broader substrate specificity.

70
Q

Which cholinesterase has a genetic variant?

A

Butyryl cholinesterase, leads to decreased activity of the enzyme.

71
Q

What are the 3 classifications of AChe inhibitors?

A

Short acting - Edrophonium

Intermediate acting - Donepezil, MG drugs

Irreversible - Malathion, Sarin, Novichok, Dyflos

72
Q

What is an alternative name for the irreversible AChe inhibitors?

A

Organophosphates

73
Q

Describe where AChe inhibitors will act.

A

AChe inhibitors will act anywhere where there is an acetylcholine synapse.

This includes:
Somatic efferent nervous system when acetylcholine is released at the NMJ acting on nicotinic receptors causing skeletal muscle contraction.

In the parasympathetic nervous system acetylcholine is released in the post-ganglionic fibre acting on muscarinic receptors causing stimulation of all the effects of the parasympathetic nervous system.

It the sympathetic nervous system acetylcholine is released in the post ganglionic fibre, acts on muscarinic receptors and stimulates sweat glands.

Acetylcholine also released in the autonomic ganglion.

74
Q

Where are Neostigmine and Pyridostigmine selective to?

A

Increased activity at the neuromuscular junction.

75
Q

Why is it essential that Neostigmine and Pyridostigmine have selectivity for the NMJ?

A

They want to be enhancing the effects at the NMJ, increasing the muscle contractility as this is where precisely the auto-antibodies are directed at the nicotinic receptors in Myasthenia Gravis.
Remember it is a long term neuromuscular disease that leads to skeletal muscle weakness, not just where acetylcholine is found.
You would not want the drugs that be binding to muscarinic receptors for example that regulates the parasympathetic nervous system as this would lead to adverse effects.

76
Q

Which drugs have selectivity to the post-ganglionic fibres?

A

Organophosphates
Physostigmine

77
Q

Describe the physiological effects of Cholinesterase inhibitors at the parasympathetic nervous system.

A

They are said to be parasympathomimetics, the effects will mimic what the parasympathetic nervous system normally does.

78
Q

Describe the cardiovascular effects of Cholinesterase inhibitors.

A

Bradycardia
Reduced cardiac output
Vasodilation due to release of Nitric Oxide

79
Q

Describe the effects on smooth muscle of Cholinesterase inhibitors.

A

There is a contraction of smooth muscle apart from vascular smooth muscle
Increase in peristaltic activity (increase in gut motility)
Bladder and bronchial contraction

(Is the respiratory failure as a result of cholinergic crisis due to constant contraction?) - but the diaphragm is skeletal muscle - still a cholinergic effect.

GO OVER THIS***

80
Q

Describe the effects on the eye as a result of Cholinesterase inhibitors.

A

Leads to pupil and ciliary muscle contraction leading to pupil constriction.
There is a decrease in intraocular pressure

81
Q

Describe the effects on glandular secretions as a result of Cholinesterase inhibitors.

A

Increase in glandular secretions including:

Saliva
Lacrimation
Bronchial secretion
Digestive enzymes

And sweating as part of the sympathetic nervous system

82
Q

What happens when Cholinesterase inhibitors are used in excess?

A

Cause a depolarisation block:
This can either have a therapeutic effect - cross the blood brain barrier and improve cognition. (Alzheimer’s)

  • cholinergic crisis

Inflammation (11 decks)

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