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Neuro II > Neuromuscular Junction Disorders > Flashcards

Neuromuscular Junction Disorders Flashcards

1
Q

The amount of ACh released into the neuromuscular junction is direction proportional to what variable?

A

concentration of Ca2+ present in the presynaptic bulb

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2
Q

Describe the overall mechanism of muscle contraction starting from the nerve impulse in the presynaptic axon.

A
  • AP propagated down axon to axon hillock
  • activation of voltage-gated calcium channels
  • influx of Ca2+ which binds to calmodulin resulting in the release of ACh into the neuromuscular junction
  • ACh binds to ACh receptors on the postsynaptic membrane
  • This causes ligand-gated sodium channels to open
  • sodium is influxed & an endplate potential is generated
  • If endplate potential is above a given safety factor, this causes an AP
  • The AP causes activation of Ca2+ channels and the depolarization lead to Ca2+ release from the T-tubules in the sarcoplasmic reticulum
  • Ca2+ will bind to Troponin C, which causes the tropomyosin to uncover myosin binding site on actin
  • this leads to actin-myosin coupling & therefore contraction
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3
Q

How is ACh stored in the axon terminal? How much is immediately available for use? Stores?

A

stored in vesicles called quanta (contain ~10,000 molecules ACh)

~1,000 quanta immediately available for release

~10,000 quanta as secondary stores - available in seconds

~100,000 quanta as tertiary stores

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4
Q

What happens to the ACh released into the neuromuscular junction?

A
  1. degraded by acetylcholine esterase into acetate & choline
    1. acetate & choline are taken back up into the synaptic bulb by active reuptake
    2. acetylcholine is re-synthesized for future use
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5
Q

What is the safety factor?

A

the difference between the threshold required to generate an action potential an the magnitude of the end plate potential (EPP)

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6
Q

Define each of the variables shown in the provided table with relation to a 3-Hz Repetitive Nerve Stimulation:

A
  • n = quanta (10,000 molecules ACh) immediately available for release
  • m = number of quanta released
  • MFAP = muscle fiber action potential
  • CMAP = compound muscle action potential
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7
Q

What pattern would you see in a 3-Hz Repetitive Nerve Stimulation for a normal subject?

A

n, m and EPP all decrease (proportionally) but a MFAP is still generated because EPP Is always above the threshold

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8
Q

What are the Neuromuscular Junction disorders seen in adults?

A
  • Myasthenia Gravis
    • Ocular
    • Generalized
  • Lambert Eaton Myasthenic Syndrome
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9
Q

What are the Neuromuscular Junction disorders seen in neonates/infants?

A
  • transient neonatal Myasthenia Gravis
  • Congenital Myasthenia Gravis
  • Botulism
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10
Q

Myasthenia Gravis is what type of condition?

A

post-synaptic autoimmune disorder

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11
Q

What is the cause of muscular weakness seen in Myasthenia Gravis? How do the symptoms of the two types di

A

circulating antibodies that block postsynaptic ACh receptors at the NMJ inhibiting the excitatory effects of ACh on nicotinic receptors

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12
Q

What are the two types of Myasthenia Gravis & how do they differ?

A
  • Ocular
    • affecting ocular muscles only
    • pupils are spared
    • ⅔ will progress to generalized MG with bulbar, respiratory & proximal > distal limb weakness
  • Generalized
    • affecting proximal > distal muscles
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13
Q

What are the symptoms of Myasthenia Gravis Syndrome?

A

fatigable weakness; worsens throughout the day

80% have fluctuating, asymmetric extraocular weakness, ptosis, weak eye closure

diplopia, dysarthria, generalized weakness

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14
Q

Why doe patients with Myasthenia Gravis often present with extaoccular weakness, ptosis & weak eye closure?

A

these are small muscles that have less number of fascicles than larger muscles, so will be spent down faster

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15
Q

What demographics are classically affected by Myasthenia Gravis?

A

Bimodal distribution

  • Females: 20-30 yr
  • Male & Female: 50-60 yr
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16
Q

Myasthenia Gravis can be associated with what other medical conditions?

A
  • Thymoma (10%)
    • epithelial cell tumor
  • Thyrotoxicosis
  • RA
  • Disseminated lupus erythematosus
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17
Q

The thymomas seen in patients with Myasthenia Gravis are associated with what antibodies?

A

anti-striational antibodies

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18
Q

What tests are performed to diagnose Myasthenia Gravis?

A
  • Anti-AChR Antibodies
    • 50% ocular & 85% generalized
    • binding, blocking & modulating
  • Anti-MuSK Antibodies
    • 10% young women with oculobulbar predominance
  • Tensilon test (Edrophonium- short acting AChesterase inhibitor)
    • keeps ACh in junction longer & decrease weakness
  • Ice Pack Test
    • put ice on eyes for 2 min → sustained 2mm decreases in ptosis
  • Repetitive Nerve Stimulation
    • decremental response
  • Single Fiber EMG
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19
Q

What pattern would you see on 3-Hz Repetitive Nerve Stimulation in a patient with Myasthenia Gravis?

A

A normal amount of quanta are released

EPP is initially low (normal was 40) and then drops because there are less ACh receptors available - Safety Factor is Low

EPP drops below the threshold potential, so a MFAP is not generated & therefore CMAP declines

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20
Q

What are the initial treatments for Myasthenia Gravis?

A
  • Steroids
    • reduces rate of conversation ocular to generalized
  • Steroid Sparing Agents
    • azathioprine & Mycophenolate mofetil (purine synthesis inhibition)
  • Thymectomy
  • ACheE Inhibition
    • pyridostigmine - symptomatic relief (NOT disease modifying)
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21
Q

When is thymemectomy indicated in patients with Myasthenia Gravis?

A
  • indicated for all patients with a thymoma
  • non-thymomatous patiens with generalized MG 18-50yr
  • NOT for thymoma patients with MuSK positive
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22
Q

What steroid sparing agents are used in refractory cases of Myasthenia Gravis?

A
  • maintenance IVIG/plasma exchange
  • rituximab- anti-B monoclonal antibody (first line anti-MUSK)
  • eculizumab- anti-C5 monoclonal antibody
  • efargtigimod- blocks neonatal Fc receptor & reduces IgG antibodies
  • cyclophospamide- alkylating agent that inhibits B & T cells
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23
Q

Why is it important to be sure of dosing when converting from P.O. medication to I.V. medication?

Specifically with pyridostigme bromide?

A

the amount drastically decreases, which can lead to overdose

with pyridostigme bromide, this can lead to cholinergic crisis

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24
Q

What is the presentation & assessment of Myasthenia Crisis?

A
  • Presentation: Respiratory Failure
    • usually in first 2 yrs of diagnosis
    • generalized muscle weakness
    • unable to handle oral secretions
    • Bedside FVC- # counted out loud in 1 minute x 100 = total volume (mL)
      • normal > 60mL/kg
      • < 20 mL/kg → need intubation
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25
Q

What are the triggers for Myasthenia Crisis? What medication should be specifically avoided?

A
  • 40% infection associated (ie. aspiration pneumonia)
  • physical stress (ie. recent surgery)
  • Medication triggers
    • aminoglycosides, quinolones, quinidine, procainamide, beta blockers, calcium channel blockers, magnesium sulfate, steroids (can worsen if increased abruptly)
    • avoid neuromuscular blockers in ICU
      • use etomidate (GABA receptor modulator)
26
Q

What is the treatment of Myasthenia Crisis?

A

IVIG of Plasma Exchange (equally effective)

& ventilator support

27
Q

What is the best way to distinguish between a Mysthenic Crisis and a Chonilergic Crisis?

A

Look at the pupils

Myasthenic Crisis: normal (mydriasis)

Cholinergic Crisis: miosis

28
Q

What is the presentation of a patient with Choinergic Crisis?

A

abdominal cramps, diarrhea, N&V Excessive secretions

generalized muscle weakness

miosis

29
Q

What is the reaction to edrophonium (Tensilon) in a Myasthenic Crisis vs. Choniergic Crisis?

A

Myasthenic Crisis: improves paralysis

Cholinergic Crisis: worsens paralysis

30
Q

What is the treatment for Cholinergic Crisis?

A

Ventilator suport & atropine

31
Q

What demographics are most commonly affected by Lambert Eaton Myasthenic Syndrome (LEMS)?

A

Male >40yr associated with malignancy (90% are small cell lung cancer); symptoms can precede the cancer by years

(female <40 yr are not associated with malignancy)

32
Q

What is the cause of LEMS?

A
  • P/Q type voltage-gated Ca2+ channel target by antibody on:
    • presynaptic motor nerve terminal
    • autonomic nerve terminal
    • cerebella purkinje cells
33
Q

What are the symptoms of LEMS?

A
  • weakness (improves with use)
  • dry mouth, sluggish pupillary reaction, erectile dysfunction
  • ataxia
34
Q

Why does weakness improve with use in LEMS?

A

repetitive use increases strength d/t increased Ca2+ entering the nerve terminal

35
Q

What are the clinical features important in the diagnosis of LEMS?

A
  • difficulty walking - worse in heat
    • slowly progressive proximal leg weakness
    • ataxia
  • decreased / absent reflexes (may increase after exercise)
  • 60% have autonomic features
    • dry mouth/eyes, postural hypotension, impotence, urinary urgency
  • strength transiently increased with sustained effort
  • VGCCA (voltage gated calcium channel antibodies)
  • Repetitive Nerve Stimulation
36
Q

Involvement of what muscles is common in MG but not in LEMS?

A

ocular, bulbar & respiratory involvement

37
Q

What pattern would you see in a 3-Hz Repetitive Nerve Stimulation for a patient with LEMS?

A

initial EPP generated is normal for # quanta released ; but b/c [Ca2+] is decreased, initial quanta released is low → initial EPP is below threshold → no MFAP generated

38
Q

What pattern would you see in a 50-Hz Repetitive Nerve Stimulation for a patient with LEMS?

A

EPP is low at baseline, but the massive stimulation is pumping Ca2+ into the presynaptic bulb faster than it can exit, so artificially pumping up the [Ca2+], so the amount of ACh released is such that the EPP reaches above the threshold and an AP is generated

Incremental response in CMAP

39
Q

What is the initial treatment for LEMS?

A
  • Look for & remove malignancy!
  • amifampridine (3,4 diaminopyridine phosphate salt)
    • blocks presynaptic potassium channels → increases openint time of available P/Q type voltage gated Ca2+ channels → greater ACh release
40
Q

How do you treat refractory LEMS?

A
  • steroids
  • azathioprine
  • plasma exchange/IVIG (less effective than with MG)
41
Q

What percent of babies born to myasthenic motheres present with transient neonatal myathenia gravis?

Cause?

A

10-20%

transplacental passage of ACh receptor antibodies

42
Q

Describe the typical presentation of a patient with transient neonatal myathenia gravis

A

onset within hours (always with in 3 days)

transient feeding difficulties, weak cry, breathing difficulties, floppiness

43
Q

What is the treatment for transient neonatal myasthenia gravis?

A

support ventilation, neostigmine

recovery within 3 weeks

44
Q

What is the cause of congenital myasthenic syndrome? What are the 3 types?

A

genetic defect

not an autoimmune disorder (does not respond to immunotherapy)

Types: presynaptic, postsynaptic, synaptic

45
Q

How do you treat congenital myasthenic syndromes?

A

patients improve on AChE inhibitors

treatment depends on subtype

no treatment to cure underlying genetic abnormality

46
Q

How can magnesium impact the neuromuscular junction?

A

hypermagnesemia blocks calcium release → inhibiting the generation of an AP

47
Q

What is a major cause of hypermagnesemia?

A

maternal administration of magnesium sulfate in treatment of eclampsia

check reflexes - if diminish, too much magnesium

48
Q

What drugs use to treat sepsis can also inhibit the neuromuscular junction transmission?

Other side effect?

A

aminogycoside

ototoxicity

49
Q

Low levels of what electrolyte can induce hypermagnesemia + facilitate aminoglycoside toxicity?

A

calcium

hypoclacemia accentuates both

50
Q

What are the 2 types of botulism?

A

food & wound

51
Q

What is the mechanism behind botulism?

A
  • SNARE proteins - impairing ability of ACh vesicles to fuse with the presynaptic membrane
  • so, the problem is with ACh release into the junction
52
Q

What is the presentation of adult foodborne botulism?

A
  • 12-14 hrs post food ingestion (sausage, carrot juice, canned food)
  • Early autonomic disturbance
    • nausea, vomiting, diarrhea
  • Bilateral cranial nerve paralysis
  • Dilated, poorly reactive pupils
  • Descending symmetrical neuromuscular weakness
    • respiratory compromise ~12-36 hrs
  • Normal sensory function
53
Q

What is the difference in presentation of a patient with adult foodborne botulism & wound botulism?

A

no GI prodrome

will have fever & leukocytosis

54
Q

What is a major differentiating symptom to distinguish between MG and Botulism?

A

dilated, poorly reactive pupils in botulism

NO pupillary involvement in MG

55
Q

What is the general age range for infant botulism & what is the usual cause?

A

2wks - 8 months

ingestion spores from soil/dust

absence of competitive bowel flora → predispose to vulnerability

56
Q

Why are breast fed infants more protected from infant botulism than formula fed?

A

clostrum in breast milk offers some protection

susceptible during transition to formula / solid food

57
Q

What type of botulinium toxin is found in honey? Infant consumption of this toxin can cause what symptoms?

A

Type B

  • Symptoms:
    • constipation (first sign)
    • lethargic, listless floppy infant
    • poor sucking, drooling & weak cry
    • dilated poorly reactive pupils
    • respiratory distress
58
Q

What is the treatment for infant or foodborne botulism?

A

antitoxin

equine heptavalent for children >1yr & adults

human-derived botulism immune globulin for <1yr

+ supportive care & mechanical ventilation as needed

59
Q

What is the treatment for wound botulism?

A

antitoxin + penicillin G/metronidazole

+ supportive care & mechanical ventilation as needed

60
Q

What antibiotics should be avoided when treating wound botulism? Why?

A

aminoglycosides - cause bacteria lysis & accelerated release of toxins into bloodstream

61
Q

Identify the pathology associated with each step in the sequence of events leading to muscle contraction

A

Neuro II (30 decks)

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