4/14 Disorders of NMJ - Corbett Flashcards
neuromuscular junction
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
nerve transmission: sequence of events
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
NMJ disorders
myasthenia gravis
basics
target(s)
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
how do antibodies cause disease?
(MG)
antibody targets
link between muscle stim and weakness
association b/w ab and ___
- 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:
- AChR (80%)
- MuSK (10)
- 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
MG
signs/symptoms
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
antibodies associated with _____
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
electrical stimulation dx
normal vs myasthenia gravis
MG tx
PYRIDOSTIGMINE: AChE inhibitor
Lambert Eaton Myasthenic Syndrome
mechanism
2 forms
dx criteria
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;
-
small cell lung-cancer assoc (50%)
- M>F, mean 60yo
- smokers
- 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
electrical stimulation in LEMS
increase with more stimulation
LEMS tx
- check for small cell lung cancer
- pharma:
- guanidine
- aminopyridines: allows depol events to last longer
myasthenia gravis
vs
Lambert Eaton Myasthenic syndrome
- pathophys
- eye sx
- association
- reflexes
- repetitive movements
organophosphate poisoning
sx mnemonics
drugs
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”)
botulism
toxin is endocytosed, cleaves SNARE proteins involved with ACh vesicle release
- symmetric nero deficits
- CN palsy
- descending weakness
- resp arrest