Myasthenia Gravis Flashcards
What is Myasthenia Gravis?
Myasthenia Gravis is an autoimmune disease due to weakness of the skeletal muscles.
- This is because the autoantibodies that are made to the nicotinic acetylcholine receptors that’s are found in the skeletal muscle, which are transmissions through the neuromuscular junction is decreased.
| V - The body makes autoantibodies, hence antibodies that are against the nicotinic acetylcholine receptors which are specifically in the NMJ which are critical in transmission of information across the synapse, hence the muscle transmission will be affected.
What are the causes and risk factors of myasthenia gravis?
- Prevalence in females peaks between 20-30 years of age
- Prevalence in males peaks between 60-80 years of age
- Risk higher in younger females compared to males
- Main cause of the autoimmune disease is unknown
What are the signs and symptoms of someone with Myasthenia Gravis?
Usually patients will present with ocular (eyes or vision related) symptoms:
- Drooping eyelids - CLASSIC SYMPTOM
- Double vision
- Restricted eye movements; which worsens when tired
Other symptoms include:
- Lack of facial expression
- Slurred speech
- Difficulties chewing
- Difficulties swallowing (dysphagia)
- Weakness in arms, legs, neck
- Shortness of breath -> Can be severe - MYASTHENIC CRISIS
What tests can be done to diagnose Myasthenia Gravis?
- Ice test
- Where you put ice on the muscle and cooling the muscle improves the symptoms - Blood tests for auto-antibodies
- Neurophysiology tests
- Electromyogram can be used to measure the muscle compound action potential in the muscle and if you repeatedly stimulate the muscle, the action potential in the muscle decreases which is diagnostic of this disease. - Endrophonium test
- Endrophonium is a short-acting cholinesterase inhibitor
- When this drug is given you see an immediate increase in muscle strength (i.e. the eyelids open) which is diagnostic
- Rarely used due to potential side effects - CAT scan
- CAT scan done to exclude thymoma (cancer)
What is the natural history of myasthenia gravis?
- It is a long-term condition
- Most patients with MG can live normal lives without significant impact on life expectancy - Severity of MG fluctuates
- Usually starts with ocular symptoms
- Hence called Ocular myasthenia gravis - Usually progresses to affect other muscles
- 80% of patients show progression from ocular MG to other muslces
- Progression can be fast or slow - Can be life-threatening
- If myasthenia crisis occurs (severe shortness of breath)
- Can cause acute respiratory failure as the diaphragm is a skeletal muscle and if were not getting transmission through the NMJ at the diaphragm, we won’t be able to breath
- May require mechanical ventilation
- MEDICAL EMERGENCY
What are the treatment options for Myasthenia Gravis?
- Acetylcholinesterase inhibitors (anticholinesterases)
- Example- Pyridostigmine
- Provides symptomatic relief; As theyre acting at the NMJ to enhance transmission through that NMJ
+ - Immunosuppressive therapy
- Oral steroids
- Other immunosuppressants e.g. Azathioprine, ciclosporine - IV immunoglobulin or plasma exchange
- For readily enhancing MG or Myasthenia Crisis - Thymectomy (resection/removal of the thymus gland)
What is the pathophysiology of Myasthenia Gravis?
NORMALLY
1. At the NMJ, the action potential comes in which opens the voltage gated calcium channels
- Calcium enters the synaptic terminal which causes the exocytosis of the Acetylcholine.
- Acetylcholine then diffuses across the synaptic cleft and interacts with receptors, nicotinic acetylcholine receptors.
- Acetylcholine acts at those nicotinic choline receptors and opens the ligand gated ion channels, which allows Na+ into the muscle cell, you get end plate potential and the action potential is let free resulting in the contraction of the muscle.
IN MG
1. If we lost the nicotinic receptors or fewer nicotinic receptors, this will impair/reduce/stop transmission
- In MG the autoantibodies will cause a loss of those receptors and in turn cause that loss of transmission across the synapse hence resulting in no contraction of muscle.
Which muscles are affected in Myasthenia Gravis?
The most affected muscles in Myasthenia Gravis are those that are in most use. Hence the more a muscle is used, the more likely it is affected by MG.
- Hence giving the classic symptoms like drooping of eyelids and lack of facial expression
Why do we inhibit acetylcholinesterase to treat Myasthenia Gravis?
- In MG we want to boost the transmission of acetylcholine so by inhibiting acetylcholinesterase, hence more acetylcholine stays around the synapse for longer which allows an increase in activity at that synapse and improves the muscle contraction.
How is acetylcholine produced?
We make the acetylcholine by cholineacetylesterase (CAT)
- We get the ACh and store it in vesicles
- The vesicles are the released and moves across the synaptic cleft and acts at our post synaptic receptors or even at pre synaptic receptors
- Acetylcholine is then broken down into choline and acetate and choline is then taken back into the pre synaptic terminal where it can then be used again to make more acetylcholine.
What happens when we inhibit the acetylcholine esterase?
If we inhibit/block the acetylcholine esterase, were no longer breaking it down into choline and acetate, hence theres more acetylcholine and prolonged presence in the synapse means that it facilitates the action and get more of the downstream of the neurotransmitter.
What are the 2 different types of cholinesterases?
- Acetylcholinesterase (AChE)
- Can be membrane bound (vesicle) (synaptic cleft) or in soluble form
- Found at Ash synapses
- Specific for ACh - Butyrylcholinesterase (BuChE)
- Widespread distribution - found in the plasma, liver, skin
- Broader substrate specificity
- Genetic variant for BuChE activity - people with this particular mutation have reduced activity
What are the 3 main groups of drugs that inhibit cholinesterase?
- Short-acting
E.g. Edrophonium - Medium duration (mainly used therapeutically)
E.g. Neostigmine, Pyridostigmine, Donepezil - Irreversible
E.g. Malathion, Dyflos, Sarin, VX, “Novichok”
What is the effect of Acetylcholinesterase inhibitors in the somatic efferent system?
In the somatic efferent nervous system, ACh is released at the NMJ to cause contraction of skeletal muscle.
So our acetylcholinesterase inhibitors will have an effect on skeletal muscle contraction.
What is the effect of Acetylcholinesterase inhibitors in the parasympathetic system?
In the parasympathetic nervous system the post ganglionic neuron relates acetylcholine acting on muscarinic receptors on target organs.
All those target organs such as the salivary glands, heart, smooth muscle, glands etc will be affected by acetylcholinesterase inhibitors.
Irreversible cholinesterase inhibitors, Physostigmine and Organophosphates have a selectivity at working at the parasympathetic synapses.
Cholinesterase inhibitors are parasympathomimetic, meaning they mimic what the parasympathetic nervous system usually does.
PARASYMPATHETIC = REST + DIGEST
