Neuromuscular Junction Disorders Flashcards by Katherine E Nordstrom

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

concentration of Ca²⁺ present in the presynaptic bulb

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

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

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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What happens to the ACh released into the neuromuscular junction?

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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What is the safety factor?

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

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

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

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

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What are the Neuromuscular Junction disorders seen in adults?

Myasthenia Gravis
- Ocular
- Generalized
Lambert Eaton Myasthenic Syndrome

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

transient neonatal Myasthenia Gravis
Congenital Myasthenia Gravis
Botulism

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Myasthenia Gravis is what type of condition?

post-synaptic autoimmune disorder

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

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

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

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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What are the symptoms of Myasthenia Gravis Syndrome?

fatigable weakness; worsens throughout the day

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

diplopia, dysarthria, generalized weakness

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

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

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What demographics are classically affected by Myasthenia Gravis?

Bimodal distribution

Females: 20-30 yr
Male & Female: 50-60 yr

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Myasthenia Gravis can be associated with what other medical conditions?

Thymoma (10%)
- epithelial cell tumor
Thyrotoxicosis
RA
Disseminated lupus erythematosus

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

anti-striational antibodies

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What tests are performed to diagnose Myasthenia Gravis?

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

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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What are the initial treatments for Myasthenia Gravis?

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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When is thymemectomy indicated in patients with Myasthenia Gravis?

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

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

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

Specifically with pyridostigme bromide?

the amount drastically decreases, which can lead to overdose

with pyridostigme bromide, this can lead to cholinergic crisis

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What is the presentation & assessment of Myasthenia Crisis?

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

* 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)

What is the treatment of Myasthenia Crisis?

IVIG of Plasma Exchange (equally effective) & ventilator support

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

Look at the pupils _Myasthenic Crisis:_ normal (mydriasis) _Cholinergic Crisis_: miosis

What is the presentation of a patient with Choinergic Crisis?

abdominal cramps, diarrhea, N&V Excessive secretions generalized muscle weakness miosis

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

Myasthenic Crisis: improves paralysis Cholinergic Crisis: worsens paralysis

What is the treatment for Cholinergic Crisis?

Ventilator suport & atropine

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

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)

What is the cause of LEMS?

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

What are the symptoms of LEMS?

* weakness (improves with use) * dry mouth, sluggish pupillary reaction, erectile dysfunction * ataxia

Why does weakness improve with use in LEMS?

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

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

* 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

Involvement of what muscles is common in MG but _not_ in LEMS?

ocular, bulbar & respiratory involvement

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

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

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

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

What is the initial treatment for LEMS?

* 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

How do you treat refractory LEMS?

* steroids * azathioprine * plasma exchange/IVIG (less effective than with MG)

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

10-20% transplacental passage of ACh receptor antibodies

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

onset within hours (always with in 3 days) transient feeding difficulties, weak cry, breathing difficulties, floppiness

What is the treatment for transient neonatal myasthenia gravis?

support ventilation, neostigmine recovery within 3 weeks

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

genetic defect not an autoimmune disorder (does not respond to immunotherapy) Types: presynaptic, postsynaptic, synaptic

How do you treat congenital myasthenic syndromes?

patients improve on AChE inhibitors treatment depends on subtype no treatment to cure underlying genetic abnormality

How can magnesium impact the neuromuscular junction?

hypermagnesemia blocks calcium release → inhibiting the generation of an AP

What is a major cause of hypermagnesemia?

maternal administration of magnesium sulfate in treatment of eclampsia check reflexes - if diminish, too much magnesium

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

aminogycoside ototoxicity

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

calcium hypoclacemia accentuates both

What are the 2 types of botulism?

food & wound

What is the mechanism behind botulism?

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

What is the presentation of adult foodborne botulism?

* 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

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

no GI prodrome _will_ have fever & leukocytosis

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

dilated, poorly reactive pupils in botulism NO pupillary involvement in MG

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

2wks - 8 months ingestion spores from soil/dust absence of competitive bowel flora → predispose to vulnerability

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

clostrum in breast milk offers some protection susceptible during transition to formula / solid food

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

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

What is the treatment for infant or foodborne botulism?

antitoxin equine heptavalent for children \>1yr & adults human-derived botulism immune globulin for \<1yr + supportive care & mechanical ventilation as needed

What is the treatment for wound botulism?

antitoxin + penicillin G/metronidazole + supportive care & mechanical ventilation as needed

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

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

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