Myasthenia Gravis Flashcards
What is Myasthenia Gravis?
Myasthenia Gravis is an autoimmune disease
characterised by weakness of the skeletal muscle
- Autoantibodies are made to the nicotinic acetylcholine
receptor in skeletal muscle - Transmission through the NMJ is decreased
What type of autoimmune disease is MG?
Organ specific autoimmune diseases
Epidemiology of MG?
Incidence 5.3/1,000,000 per year
* Prevalence 77.7/1,000,000
* Mortality 0.1-0.9/1,000,000 per year
The numbers are likely to be underestimates particularly due to lack of
diagnosis in older patients
Signs and symptoms of MG?
Usually patients present with ocular symptoms
- Drooping eyelids (ptosis)
- Double vision (diplopia)
- Restricted eye movements
- Worsen when tired
Other symptoms that do not involve Ocular symptoms?
Lack of facial expression
* Slurred speech
* Difficulties chewing
* Difficulties swallowing (dysphagia)
* Weakness in arms, legs, neck
* Shortness of breath
* Can be severe – myasthenic crisis
Why is it difficult to diagnose MG?
Can be difficult to diagnose since symptoms fluctuate. In older patients there are similarities to other conditions
What tests are carried out in MG?
Ice test
* Cooling the muscle improves symptoms
Blood test for auto-antibodies
Neurophysiology
* Electromyogram measures the muscle compound action potential in response to repeated stimulation
* See a decrease in the size of the muscle response
Edrophonium test
* Edrophonium is a short-acting cholinesterase inhibitor
* Injection of edrophonium causes increase in muscle strength (ptosis is reversed)
* Rarely used due to side effects
CAT scan to exclude thymoma
What are the natural history of MG?
Long-term condition
- Severity fluctuates
- Usually starts with ocular symptoms (Ocular myasthenia gravis)
- Usually progresses to affect other muscles (80% of patients show progression from ocular MG, Progression can be rapid (weeks) or slow (years))
- Can be life-threatening
- Myasthenic crisis
- Affects 20% of patients at some point in their lives
- Acute respiratory failure
- Requires mechanical ventilation
What the treatment for MG?
Acetylcholinesterase inhibitors (anticholinesterases)
* Eg. Pyridostigmine
* Symptomatic relief
- Immunosuppressive therapy
- Oral steroids
- Other immunosuppressants Eg. Azathioprine, ciclosporin
- Intravenous immunoglobulin or plasma exchange
- For rapidly deteriorating MG or myasthenic crisis
- Thymectomy
The pathophysiology of MG?
Myasthenia Gravis is an autoimmune
disease
- Characterised by muscle weakness* A disease of the neuromuscular junction (NMJ)
- Impaired transmission at the NMJ leads to the muscular weakness
- Auto-antibodies are made to the muscle nicotinic acetylcholine receptors
What muscles are most affected in MG?
The most affected muscles are those that are in most use (use dependent)
Giving classic symptoms such as ptosis (drooping of the eyelids) and lack of facial expression
Events that occur at the NMJ?
An action potential opens the voltage-gated Ca2+ channel and calcium goes into the synaptic terminal
Exocytosis of Acetylcholine, which causes it to diffuse to across the synaptic cleft and interacts with the receptors
At the NMJ Acetylcholine is released which acts at the nicotinic receptor opening the ligand gated ion channel causes sodium into the muscle cell then the AP therefore muscle contraction.
What happens in order to terminate action at the NMJ in MG?
Action of acetylcholinesterase. Acetylcholinesterase in the post-synaptic membrane breaks down Acetylcholine and terminating the contraction.
This gets rid of AC which causes muscle relaxation
In MG there is boost of transmission by inhibiting the acetylcholinesterase therefore more AChE stays around the synapse for longer which allows the increase in activity at the synapse and this improves muscle contraction.
Cholinesterase Inhibitors?
The action of acetylcholine in the synaptic cleft is
terminated by acetylcholinesterase (AChE)
- Inhibition of AChE causes an increase in ACh at the
synaptic cleft prolonging its activity - Several therapeutic agents act by inhibiting
cholinesterase activity
eg: – Neostigmine, pyridostigmine – myasthenia gravis
-Malathion – insecticide (headlice)
– Donepezil – Alzheimer’s disease
What are the 2 types of Cholinesterase?
-Acetylcholinesterase (AChE)
– Can be membrane bound (synaptic cleft) or in soluble form
(pre-synaptic terminal; cerebrospinal fluid)
– Found at ACh synapses
– Specific for ACh
– Butyrylcholinesterase (BuChE)
– Widespread distribution – plasma, liver, skin
– Broader substrate specificity
– Genetic variant for BuChE activity (reduced activity)
What are the 3 drug classes that inhibit Cholinesterase?
3 main groups:
– Short-acting eg. Edrophonium
– Medium duration eg neostigmine, pyridostigmine,
donepezil - used therapeutically
– Irreversible eg malathion, Dyflos, Sarin, VX,
“Novichok’
What are the effects of cholinesterase inhibitors (CV & Smooth muscle?
Neuromuscular junction (neostigmine, pyridostigmine)
– Increase in twitch tension due increased acetylcholine
Parasympathetic synapses (post-ganglionic) eg.
Physostigmine, organophosphates- Irreversible
Cholinesterase inhibitors are parasympathomimetic- mimic what the parasympathetic usually does i.e.
Cardiovascular
– Bradycardia
– ↓cardiac output
– Vasodilation (via release of NO)
→ ↓ blood pressure
Smooth muscle
– Contraction of smooth muscle (exception - vascular SM)
* ↑ peristaltic activity
* Bladder contraction
* Constriction of bronchioles
If you block AchE then you have more Ach so more of the parasympathetic system
What can too much acetylcholine lead to?
Depolarisation block!
- Larger doses can cause depolarization block of
autonomic ganglia and the NMJ due to excessive ACh - They also have central effects if they can cross the
blood brain barrier. Effects include: - Improved cognition (therapeutic)
- Convulsions, unconsciousness, respiratory failure
(toxicity)
What are the effects of cholinesterase inhibitors ( Eye & Glands)?
Eye
– Pupil constriction
– constriction of ciliary muscle (accommodation)
→ ↓ intraocular pressure (glaucoma)
- Glands – ↑ secretion (salivation, lacrimation, bronchial
secretion, digestive enzymes, sweating) - NB Sweat glands – cholinergic synapse, sympathetic
nervous system (the odd one out…)
What are the managements of MG?
- Avoid disease triggers
- Symptomatic treatment to produce - minimal symptoms + minimal drug side effects
- Immunosuppressant drugs
- Immunomodulatory treatments
What are some of the triggers of MG?
This can be anything that exacerbates muscle weakness:
- Infection
- Stress or trauma
- Thyroid dysfunction
- Withdrawal of acetylcholinesterase inhibitors
- Rapid introduction or increase of corticosteroids
- Anaemia
- Electrolyte imbalances
- Medicines
Some medicinal triggers that interfere with neuromuscular transmission in MG?
Phenytoin
carbamazepine
Antimuscarinic agents
Hydroxychloroquine
Lithium
Some medicinal triggers that increase muscle weakness in MG?
Magnesium causing hypermagnesemia
Benzodiazepines
Beta-blockers
Diuretics
Verapamil
Statins
What are symptomatic treatments of MG?
Oral acetylcholinesterase inhibitor
* Pyridostigmine (neostigmine used less due to shorter duration of action)
Provide a variable improvement in strength
Dosing – starting 15mg QDS with food
* Assess cholinergic s/e
* Typical maintenance 60mg four to six times a day
Adverse effects – dose dependent and predictable (nicotinic and muscarinic effects):
- Nicotinic effects – muscle and abdominal cramps
- Muscarinic – gut hypermobility (cramps and diarrhoea), increased sweat/salivations/lacrimation, hypotension, bradycardia, miosis, urinary incontinence,
increased bronchial secretions and tachypnoea
