4/14 Disorders of NMJ - Corbett Flashcards

1
Q

neuromuscular junction

A

motor neuron axon synapses with skeletal muscle

  • loses myelin sheath, divides into terminal boutons containing sm clear vesicles of ACh
  • endings fit into junctional folds, form specialized motor end plate
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2
Q

nerve transmission: sequence of events

A

1. AP arrives at NMJ

  • Ca influx → phosphorylation of synapsins → ACh vesicles released

2. ACh diffusion to Nm receptors (nicotinic cholinergic)

  • Na influx → depol → muscle contraction

3. acetylcholinesterase activated

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3
Q

NMJ disorders

A
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4
Q

myasthenia gravis

basics

target(s)

A

antibody-mediated disease of NMJ

  • target: Ach nicotinic postsynaptic receptors
  • abs present in 85% of cases
    • change morphology of synapse → NMJ folds flatten out
  • another target: MuSK (muscle specific Tyr kinase)
    • affects receptor trafficking so fx is diminished

F>M (3:2) with bimodal age peak

  • F: 20-30
  • M: 50-60
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5
Q

how do antibodies cause disease?

(MG)

antibody targets

link between muscle stim and weakness

association b/w ab and ___

A
  • accelerate turnover of AChRs by mech involving cross-linking and rapid endocytosis of receptors
  • damage to postsynaptic muscle membrane by antibody in collaboration with complement → blockade of active site of AChR

targets:

  1. AChR (80%)
  2. MuSK (10)
  3. Lrp4

more the muscle is used/stimulated → less ACh released

  • combined with loss of AChR? →→→ the more freq the muscle is used, the more weakness manifests itself

pathogenic anti-AChR autoantibodies associated with thymic abnormalities

  • 10% MG have thymoma (thymic epi cells)
  • 65%, esp young, have thymic hyperplasia
    • B cell follicles in thymus
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6
Q

MG

signs/symptoms

A

specific muscle weakness (vs generalized weakness)

  • extraocular muscle weakness (diplopia) or ptosis
    • initially? 50. eventually? 90.
  • bulbar muscle weakness (MuSK) → alters speech, swallowing, voice
  • limb weakness (usually WITH ocular sx; more severe prox than dist)
    • distinguishes from Lambert Eaton!
    • almost always starts from head/neck → extremities

weakness chars

  • least severe in morning → worse over day
  • incr w exertion
  • progresses over weeks/months, with exacerbations and remissions
    • triggers (sunlight, surgery, immunization, emotional stress, etc) for exacerbation
  • ocular → facial → bulbar → trunk/limb
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7
Q

antibodies associated with _____

A

pathogenic anti-AChR autoantibodies associated with thymic abnormalities

  • 10% MG have thymoma (thymic epi cells)
  • 65%, esp young, have thymic hyperplasia
    • B cell follicles in thymus
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8
Q

electrical stimulation dx

normal vs myasthenia gravis

A
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9
Q

MG tx

A

PYRIDOSTIGMINE: AChE inhibitor

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10
Q

Lambert Eaton Myasthenic Syndrome

mechanism

2 forms

dx criteria

A

mech: impaired ACh release from motor nerve terminal

  • autoantibodies directed against voltage-gated Ca channels on presynaptic motor nerve term
    • loss of fxal VGCCs
    • diminished nt release

two forms;

  1. small cell lung-cancer assoc (50%)
    • M>F, mean 60yo
    • smokers
  2. general autoimmune response
    • M=F, two age peaks
    • no corr with smoking

dx:

  • proximal muscle weakness
    • prox leg muscle weakness (95): difficulty rising from chair, climbing stairs, walking
    • arms too; prox → dist
    • 30% get ocular and bulbar, but almost all get generalized weakness first
  • autonomic sx
    • dry mouth
    • ED, constipation, micturition difficulty, etc
  • reduced tendon reflexes
  • VGCC antibody detection
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11
Q

electrical stimulation in LEMS

A

increase with more stimulation

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12
Q

LEMS tx

A
  • check for small cell lung cancer
  • pharma:
    • guanidine
    • aminopyridines: allows depol events to last longer
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13
Q

myasthenia gravis

vs

Lambert Eaton Myasthenic syndrome

  • pathophys
  • eye sx
  • association
  • reflexes
  • repetitive movements
A
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14
Q

organophosphate poisoning

sx mnemonics

drugs

A

acetylcholinesterase inhibitors → excess ACh in synapse

SLUDGE

  • salivation, lacrimation, urinary incont, diarrhea, GI cramps, emesis

DUMBELS

  • diarrhea, urination, miosis, bronchospasm/bronchorrhea,emesis, lacrimation, salivation

atropine: blocks ACh interaction with receptor

pralidoxime: regenerates AChE BUT has to be delivered quick (bc mech is to prevent “aging”)

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15
Q

botulism

A

toxin is endocytosed, cleaves SNARE proteins involved with ACh vesicle release

  • symmetric nero deficits
    • CN palsy
    • descending weakness
    • resp arrest
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16
Q

tetanus

A

toxin blocks release of inhib nt

  • hits inhibitory motor neurons and causes constitutive activation of motor neurons → spasm

sx:

  • tonic contractions of sk muscle, intermittent spasm
  • 50% trismus (lockjaw)
  • autonomic hyperactivity: irritability, sweating, tachycardia, arrhythmias
17
Q

botulinum toxin vs tetanus toxin

sites of action

A