B6-058 CBCL Trouble at the Junction Flashcards
list the anatomic possibilities for a lesion causing weakness from proximal to distal
motor cortex
internal capsule
brainstem
corticospinal tract (in spinal cord)
anterior horn cell
nerve roots
spinal nerves
plexus
peripheral nerves
neuromuscular junction
skeletal muscle
protein that plays a role in the coordination of clustering acetylcholine receptors on the postsynaptic side
MuSK
what is the key function of MuSK?
clustering acetycholine receptors on the motor end plate
what is the sensitivity of repetitive nerve stimulation for generalized MG?
75-80%
what is the sensitivity of repetitive nerve stimulation for occular MG?
15-45%
what percentage of patients with generalized MG have AChR Ab?
80-90%
what percentage of patients with generalized MG have anti-MuSK antibodies?
4-5%
rapid acting therapies used to control MG during a myasthenic crisis [2]
IVIG
plasma exchange
first line treatment for MG patients that do not adequately respond to pyridostigmine
prednisone
cholinesterase inhibitor used for symptomatic management of MG
pyridostigmine
drug that is particularly effective in MuSK MG patients who did not respond to pyridostigmine and prednisone
rituximab
MG patients that receive […] have less severe disease symptoms and require less prednisone
thymectomy
**regardless of whether thymoma is present
in LEMS, loss of voltage gated calcium channels results in…
decreased release of acetylcholine containing vesicles
nerve conduction shows low amplitude motor potentials and >100% increase in amplitude after 10s of exercise
LEMS
rapid repetitive nerve stimulation at 10-50 Hz frequently shows increment of >100%
LEMS
sensory nerve conduction should be […] in LEMS patients
unaffected
85-95% of LEMS patients have autoantibodies to
voltage gated calcium channels
associated with autonomic features
LEMS
**dry mouth, ED, sluggish pupillary response
dry mouth
erectile dysfunction
sluggish pupillary response
LEMS
associated with small cell lung cancer
LEMS
associated with thymoma
MG
postsynaptic NMJ disorder
MG
presynaptic NMJ disorder
LEMS
associated with ocular and bulbar symptoms
MG
associated with proximal weakness in lower extremities
LEMS
describe the first steps of management of LEMS patients [3]
- screen for/treat SCLC
- amifampridine
- immunomodulatory therapy
cause hydrolytic cleavage of SNARE proteins essential for presynaptic calcium mediated vesicle exocytosis
botulinum toxin
binding and accelerated internalization of the postsynaptic acetylcholine receptor
MG
binding and accelerated internalization of the presynaptic voltage-gated calcium channel
LEMS
what part of the nervous system is not affected by botulinum toxin
CNS
would you expect to see seizures in a patient with botulism?
no, spares the CNS
presynaptic toxin mediated disease
botulism
presynaptic immune mediated disease
LEMS
postsynaptic immune mediated disease
MG
hereditary disorders of neuromuscular transmission that can affect presynaptic, synaptic, or post synaptic NMJ
congenital mysathenic syndrome
proximal to distal anatomic sequence of the motor unit
anterior horn cell
motor axon
motor axon twig branches
NMJ
muscle fibers
have a specialized synapse with muscle fibers
lower motor neurons
relay excitatory electrical signals down through the motor axon
lower motor neurons
decussate in the brainstem at the level of the medulla
upper motor neurons
originate in the frontal lobe cortex
upper motor neurons
upper motor neurons synapse with lower motor neurons at the
anterior horn of the spinal cord
cardinal manifestations of lower motor neuron weakness
muscle atrophy
hypotonia
diminished/absent reflexes
cardinal manifestations of upper motor neuron weakness
preserved muscle bulk
spastic muscle tone
hyperreflexive
positive Babinski reflex in adults indicates damage to
upper motor neuron
sequence of event during neuromuscular transmission:
- motor axon depolarization
- voltage gated calcium channel activation
- influx of calcium on motor axon
- vesicle fusion with presynaptic membrane
- ACh release into the NMJ
- activation of the ligand gated AChR on the muscle membrane
- sodium ion influx into the muscle sarcolemma
- calcium release from endoplasmic reticulum
- activation of actin-myosin contraction
bind and block ACh receptors on postsynaptic membrane
ACh-R Ab
reduced end plate potentials below the minimum necessary to activate muscle contraction
MG
interfere with NMJ development and maintenance leading to endplate degradation and blocking of NMJ
MuSK Ab
protein that directs aggregation of AChR on the muscle during development
agrin
for [….] studies, a peripheral nerve is stimulated with an electrical pulse and the evoked potential is recorded over a distal muscle innervated by the stimulated one
motor nerve conduction studies
for [….] studies, a peripheral nerve is stimulated with an electrical pulse and the evoked potential is recorded over a proximal or distal sensory fibers innervated by the stimulated one
sensory nerve conduction studies
key bioelectric potential characteristics analyzed during nerve conduction studies [3]
distal latency
amplitude
conduction velocity
[…] greatly influences the accuracy of nerve conduction studies
technical factors
**produces false positive/negative
what percentage of patients with ocular MG have AChR Ab?
40-50%
what degree of decrement is expected on RNS studies in patients with MG?
> 10%
**must be reproducible
thymectomy is an evidence based treatment strategy for patients with what type of MG?
AChR Ab MG
when should thymectomy be performed in an eligible patient?
after disease is in control
**if not controlled, there is increased risk of myasthenic crises
autoantibodies found to be pathogenic in MG patients [3]
AChR Ab
MuSK
LRP4 Ab
CMAP decrement >10% is associated with
MG
CMAP increment is associated with
LEMS
organized protein secreted from the motor nerve terminal
agrin
agrin binds to […] which forms a receptor complex with […]
LRP4
MuSK
agrin signal is transmitted through […], Dok-7, and rapsyn to promote the accumulation, organization, and clustering of AChR
MuSK
all patients diagnosed with MG should have chest imaging to evaluate for
thymoma
MOA of pyridostigmine
inhibition of the hydrolysis of ACh within the synapse
**enhances availability for binding
the AChR has a central pore that can open and allow […] entry to the sarcolemma
sodium
the AChR has […] binding sites
2
opening of the AChR creates the endplate potential to initiate
muscle fiber action potential
hyperreflexia
spasticity
plantar extensor sign
upper motor neuron dysfunction
fatiguable weakness with sustained upward gaze is associated with
MG
slurred speech
swallowing difficulty
are associated with
MG
what is the correct path of electrical and chemical activation along a motor unit?
anterior horn cell
motor axon
axon twigs
NMJ
muscle fibers
assesses for evidence of impairment of neuromuscular transmission from motor nerve endings to skeletal muscle tissue
RNS (repetitive nerve stimulation)
commonly used prednisone sparing agent
azathioprine
first line immunosuppressant used for MG
prednisone
drug frequently used for symptom management of MG
pyridostigmine
side effects of azathioprine [2]
hepatotoxicity
bone marrow suppression
side effects of prednisone
weight gain
fluid retention
hyperglycemia
osteoporosis
most common side effect of rituximab
injection site reaction
proximal weakness
autonomic dysfunction
diminished relexes
LEMS
most common malignancy associated with LEMS
SCLC
low motor amplitude but normal sensory amplitude would suggest..
LEMS
EMG shows active denervation
ALS
associated with voltage gated calcium channel antibodies
LEMS
post exercise increased of CMAP amplitudes
LEMS
fasciculations are associated with
ALS
slows acetylcholine breakdown in the synaptic cleft and reduces myasthenic symptoms
pyridostigmine
reversible cholinesterase inhibitor
pyridostigmine
what is the MOA of the botulinum toxin?
hydrolytic cleavage of different SNARE proteins
gram positive, rod shaped anaerobe
C. botulinum
C. botulinum has the ability to differentiate into […] in stressful environmental conditions
inert endospores
why can home canning put you at risk of foodborne botulism?
C. botulinum spores are heat resistant
C. botulinum spores can be destroyed at […] C for 5 min
120 degrees C
most common NMJ disorder
MG
autoantibodies to postsynaptic ACh receptor
MG
in MG, bulbar muscle weakness causes [2]
dysphagia
difficulty chewing
in MG, respiratory muscle weakness causes [1]
dyspnea
in MG, fatiguable weakness causes [3]
ptosis
diplopia
proximal weakness
in MG, the reflexes are
spared
in LEMS, the reflexes are
hyporeflexive
[MG or LEMS] worsens with muscle use
MG
[MG or LEMS] better with muscle use
LEMS
associated with thymoma/thymic hyperplasia
MG
associated with SCLC
LEMS
potassium channel blocker that blocks K+ from exiting the motor axon, prolonging depolarization
amifampridine
amifamprine is used for symptom management of
LEMS
flaccid limb weakness
fasiculations
atrophy
hyperreflexia
ALS
terminal complement inhibitors [2]
eculizumab
raulizumab
selective B cell depleting agent that suppresses humoral immunity
rituximab
neonatal Fc receptor inhibitor used in MG treatment
Efgartgimod
subacute proximal limb weakness is associated with
LEMS
