Myasthenia Gravis

    Cards (23)

    • Myasthenia Gravis
      It is an autoimmune disease characterised by the weakness of the skeletal muscle
      Autoantibodies are made to the nicotinic acetylcholine receptor in skeletal muscle
      • Transmission through the neuromuscular junction is decreased
    • Aetiology
      Age
      Different distribution between males and females
      For females the peaks are between 20-30 years
      For males - peaks are between 60-80 years
      The risk is higher in younger females compared to males
      Cause of the autoimmune disease is largely unknown
    • Signs and Symptoms
      Usually patients present with ocular symptoms Usually patients present with ocular symptoms Usually patients present with ocular symptoms Usually patients present with ocular symptoms
      • drooping eyelids (ptosis)
      • Double vision (diplopia)
      • Restricted eye movements ( worse when tired)
      Also includes - lack of facial expression, difficulties chewing Difficulty swallowing (dysphagia), weakness in arms, legs and neck, SOB - can be severe myasthenic crisis
    • Tests
      Can be difficult to diagnose since symptoms can fluctuate
      In older patients there are similarities to other conditions
      Cause of the disease is largely unknown
      Ice test
      • simple
      • cooling the muscle improves symptoms
      Blood test for autoantibodies
    • Test 2
      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 used to exclude thymoma
    • Natural history
      Long term condition
      • most patients can live normal lives without significant impact on life expectancy
      Severity fluctuates
      Usually starts with ocular symptoms
      Then progresses to affect other muscles - 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
    • Treatment
      Acetylcholinesterase inhibitors e.g. Pyridostigmine (symptomatic relief)
      Immunosuppressive therapy - oral steroids
      • other immunosuppressive agents - e.g. Azathiprine, Ciclosporin
      Intravenous immunoglobin or plasma exchange
      • for rapidly deteriorating MG or myasthenic crisis
      Thymectomy - remove thymus gland
    • Pathophysiology
      Characterised by muscle weakness - a disease of the neuromuscular junction NMJ
      Impaired transmission at the NMJ leads to the muscular weakness
      Autoantibodies are made to the muscle nicotinic acetylcholine receptors
    • Pathophysiology 2 

      Action potential travels down the motor neuron
      opens voltage gated calcium channels
      calcium goes into the synaptic terminal
      • This causes the exocytosis of the acetyl choline which then diffuses across the synaptic cleft and interacts with Nicotinic acetylcholine receptors
      • It opens the ligand gated ion channels that allows sodium into the muscle cell - causes muscle contraction
    • MG
      The most affected muscles are the ones that are in most use giving ptosis and lack of facial expression
    • Choline esterase
      The action of acetylcholine in the synaptic cleft is terminated by acetylcholine esterase
      Inhibition of AcHE causes an increase in ACH at the synaptic cleft prolonging its activity
      Several therapeutic agents act by inhibiting cholinesterase activity e.g. Neostigmine, pyridostigmine
    • Function of choline esterase
      there are two types of choline esterase
      • Acetylcholine esterase
      • Butryrylcholine esterase
      AcHE - can be membrane bound (synaptic cleft) or in soluble form (pre-synaptic terminal, cerebrospinal fluid)
      • found at ACH synapses
      • specific for Ach
    • Function of choline esterase
      There are two types of choline esterase
      BuCHe - widespread distribution - plasma, liver, skin
      broader substrate specificity
      genetic variant for BuCHe activity ( reduced activity)
    • Inhibit cholinesterase
      There are 3 main groups
      Short acting - Edrophonium
      Medium duration - e.g. neostigmine, pyridostigmine, donepezil
      Irreversible e.g. malathion, Novichok
    • Effects
      Parasympathetic synapses (post ganglionic) e.g. organophosphates
      Cholinesterase inhibitors are parasympathomimetic - mimics the parasympathetic nervous system usually does
    • Parasympathetic
      • decreased heart rate
      • no effect on blood vessels
      • bronchi constriction
      • increased motility of the GIT (sphincter relaxation)
      • contraction of bladder
      • Contraction of pupils
      • secretion of sweat
    • Effects of choline esterase inhibitors
      Cardiovascular
      • bradycardia - slower heart rate
      • decreased cardiac output
      • vasodilation of blood vessels by nitric oxide- leads to decreased blood pressure
      Smooth muscle
      • increased peristaltic activity, gut motility increase
      • bladder contraction ( released urine)
      • constriction of bronchioles
    • Effects 2 

      Eye
      • pupil constriction
      • constriction of ciliary muscle
      • decreased intraocular pressure (glaucoma)
      Glands
      • increased secretion ( saliva, digestive enzymes, sweating)
    • Effects
      • larger doses can cause depolarisation block of autonomic ganglia and the NMJ due to excessive Ach
      • central effects if crossing the BBB- includes improved cognition( therapeutic) convulsions, unconsciousness and resp failure (toxicity)
    • Which receptor is targeted by auto antibodies in myasthenia gravis?
      The nicotinic acetylcholine receptors
    • Pyridostigmine is an example of which class of drugs?
      Acetylcholinesterase inhibitors
    • What is a side effect of acetylcholinesterase inhibitors?
      Diarrhoea
    • Where is the enzyme acetylcholinesterase found?
      They are found in the NMJ, in synaptic clefts where it breaks down the neurotransmitter acetylcholine.
      After it has transmitted a nerve signal to a muscle
      This ensures that the signal is terminated properly and prevents continuous muscle stimulation.
      Found in CNS and peripheral nervous system and AcHE helps maintain acetylcholine levels in the synaptic cleft for proper neural signalling