Myasthenia Gravis

Question 1

myasthenia gravis

Answer 1

• Autoimmune disease in which autoantibodies destroy Ach receptors.
• May be transmitted vertically from affected mother.
• Treatment with cholinesterase blockade (neostigmine) allows Ach to accumulate overcoming receptor deficit. (The neurotransmitter stays in the gap longer and is available for interaction with the post synaptic cell)
• Discovered accidentally through animal research on rabbits. (They were looking for acetylcholine receptors, When they went to check on the rabbits, they were all paralyzed, In mammals, the acetylcholine receptor is highly preserved (shared between species), The antibodies they were generating were attacking the rabbits receptors)

Question 2

how common is myasthenia gravis

Answer 2

• Harrison’s: “not rare”
• 1-7/10,000 – this is not as common as cystic fibrosis, but its fairly common
• Bimodal: F20-40, M50-60 – this is like virtually all autoimmune disorders
• F>M, 3:2

Question 3

hallmark of MG

Answer 3

• Progressive weakness and fatigability – it’s easy for them to feel fatigued
• Weakness improves p rest period
• Weakness increases with repeated use – the types of things that require sustained contraction are difficult for MG pts (Posture, driving car, etc. )
• Preference for certain muscle groups: eyes, eyelids, facial expression, chewing, swallowing, Impacted at a greater rate than other muscle groups
• Diplopia and ptosis are common first complaints

Question 4

cause of MG

Answer 4

• Weakness from defect of transmission to skeletal muscles
• Fundamental defect = Loss of acetylcholine receptors by binding of autoantibodies to receptor or muscle cell proteins (muscle-specific kinase) with flattening of post-synaptic folds. (The presynaptic cell (LMN) is completely normal. Its release of NT is normal. The pathology is ALL ON THE MUSCLE SIDE!!! The nervous system is normal!!)
• Release of Ach normal

Question 5

three mechanisms

Answer 5

1. Cross linking and rapid endocytosis leads to accelerated turnover of receptors (Receptor gets bound up and pulled back into the muscle cell which creates a more rapid turnover of receptors than the muscle cell is capable of keeping up with so that depletes the pool of NT receptors
2. Blockade of active sites on Ach receptor (NT cant bind and stimulate the receptor)
3. Damage to post-synaptic muscle membrane by antibody in complement mediated process. (Abs target immune response to muscle cell membrane and cause damage)

Question 6

LMN lives in anterior horn of the SC - myelinated

Answer 6

Resting membrane potential of -75mv

Question 7

Effect of excess stimulation

Answer 7

• Normal muscle activities require more stimulation,
• Excess stimulation decreases available pool of neurotransmitter,
• Reduce transmitter release results in less stimulation of muscle target,
• Result is increasing weakness = “myasthenic fatigue”

Question 8

pathogenesis of MG

Answer 8

• Unknown, possibly viral infection with production of cross reacting autoantibodies
• M:F = 2:3
• Ach receptors must be reduced to 30% for symptoms
• Smooth and cardiac muscles unaffected
• 75% have thymus abnormality and many improve with thymectomy (Thymus is where T cells go to get educated! If a person has myasthenia gravis and you remove it, often the myasthenia gravis goes away)

Question 9

role of the thymus

Answer 9

• Poorly understood
• Abnormal in 75%
• Hyperplastic in 65% (possible differences in age of onset)
• Thymic tumors (thymomas) 10%
• One theory is that muscle like cells in the thymus with Ach receptors may provide antigen and trigger autoimmune response in thymus
• The older you are at diagnosis, the more likely you are to have a persistent thymus and an abnormality

Question 10

symptoms of MG

Answer 10

• Weakness of eye muscles
• Occ difficulty swallowing or slurring of speech – muscles of mastication
• Ptosis
• Diplopia
• Gait instability
• SOB
• Symptoms aggravated by emotional/physical stress (illness, menstruation, etc)
• Limb weakness proximal, often asymmetric with DTRs preserved

Question 11

physical findings of MG

Answer 11

• PE often normal – unless you have a suspicion for this diagnosis
• Mild early symptom: inability to maintain superior gaze, ptosis (Look up at the ceiling for 2 minutes)
• Ice pack test positive approx 80% (cool affected area for 2 minutes, ptosis resolves) (Cooling make nerve conduction better)

Question 12

testing for MG

Answer 12

• Antibodies in blood 85% - GOLD STANDARD
• Electromyographic testing - low frequency induces reduced amplitude
• Edrophonium testing: Rapid onset (30s), short duration (5 min) acetylcholinesterase inhibition increases pool of available ACh. Improvement of symptoms immediate (also in ALS). Now used when antibody testing is negative. (Very short halflife AchE blocker!! Used to be the gold standard but now the AB test is gold standard)
• Neostigmine longer acting - can be used to verify (Has a much longer half life, Can also be used for one more test – if you give a dose of neostigmine you should see hours of relief or lessened fatigability)

Question 13

treatment of MG

Answer 13

• Many cases resolve spontaneously (1/3)
• Pharmacologic tx with cholinesterase inhibition and steroids
• Non-pharmacologic therapy with PT, etc – keeping muscles strong, etc. (Acetylcholinesterase inhibition, Thymectomy can be curative! Immunosuppression, Plasmapheresis – pull the Abs out of the blood)
• Intravenous Immunoglobulin (IVIG)

Question 14

myasthenic crisis

Answer 14

• Exacerbation of weakness sufficient to endanger life
• Usually via respiratory failure (diaphragm)
• Cholinergic crisis possible with excessive med use– must be stopped
• MCC = infection
• Drugs with cholinergic or anti-cholinergic potential should be used carefully or not at all. (Atropine, Parkinson meds)
• Also possible post-thymectomy, pre-surgical steroid treatment may reduce incidence (You don’t want to trigger a crisis by doing the surgery itself)

Question 15

alternative therapies

Answer 15

• Internet claims about large doses of vitamins for MG patients
• Vitamin K. Vitamin K may have a regulatory effect on myasthenia gravis. This fat-soluble vitamin has been shown to decrease levels of the pro-inflammatory cytokine interleukin-6 (Reddi K et al 1995). This cytokine is involved in myasthenia gravis pathogenesis and correlates with acetylcholine receptor antibody production
• Electroacupuncture warming therapy demonstrated a 93% effective rate when paired with pharmacologic treatment (pyridostigmins and prednisone) compared to 70% for meds alone in 1 study of 60 patients
• IL-4 levels were lower in observation group