Neuromuscular Junction Disorders Flashcards
The amount of ACh released into the neuromuscular junction is direction proportional to what variable?
concentration of Ca2+ present in the presynaptic bulb
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
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
What happens to the ACh released into the neuromuscular junction?
- degraded by acetylcholine esterase into acetate & choline
- acetate & choline are taken back up into the synaptic bulb by active reuptake
- acetylcholine is re-synthesized for future use
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)
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
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
What are the Neuromuscular Junction disorders seen in adults?
- Myasthenia Gravis
- Ocular
- Generalized
- Lambert Eaton Myasthenic Syndrome
What are the Neuromuscular Junction disorders seen in neonates/infants?
- transient neonatal Myasthenia Gravis
- Congenital Myasthenia Gravis
- Botulism
Myasthenia Gravis is what type of condition?
post-synaptic autoimmune disorder
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
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
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
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
What demographics are classically affected by Myasthenia Gravis?
Bimodal distribution
- Females: 20-30 yr
- Male & Female: 50-60 yr
Myasthenia Gravis can be associated with what other medical conditions?
- Thymoma (10%)
- epithelial cell tumor
- Thyrotoxicosis
- RA
- Disseminated lupus erythematosus
The thymomas seen in patients with Myasthenia Gravis are associated with what antibodies?
anti-striational antibodies
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
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
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)
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
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 Fc receptor & reduces IgG antibodies
- cyclophospamide- alkylating agent that inhibits B & T cells
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
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
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
