Neuromuscular Junction.txt

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Neuromuscular Junction.txt
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  1. Neuromuscular Junction Physiology
    • Acetyl CoA + choline -> acetylcholine (ACh): catalyzed by choline acetyltransferase (ChAT)
    • ACh packaged into besicles in discrete units called quanta
    • Quanta are located in 3 separate stores: presynaptic nerve terminal lined with active zones which are specific sites on membrane where vesicles attach and release ACh into synaptic cleft
  2. Synaptic Cleft
    • Space between nerve terminal and depression in the postsynaptic membrane into which the terminal fits
    • Site of hydrolysis of ACh by acetylcholinesterase (AChE)
  3. Post-synaptic membrane
    • Region of muscle fiber membrane across from the nerve terminal, a.k.a. endplate: 1 endplate per fiber, number increases with reinnervation
    • Contains multiple infoldings called secondary clefts: nicotinic ACh receptors concentrated on crests of folds; AChE concentrated in depths of clefts
    • ACh receptor is a transmembrane glycoprotein which binds 2 ACh molecules, opening a central channel in the receptor for a few sec, allowing Na+ to enter down its electrochemical gradient
  4. AP Potential invades and depolarizes nerve terminal
    • Voltage-gated Ca channels open, allowing influx of Ca
    • CA-dependent binding of vesicles to terminal membrane occurs: relatively slow, lasts 0.5 sec (of total 0.75msec for NMJ transmission)
    • Near-synchronous release of up to 200 quanta: number of quanta released proportional to concentration of Ca
  5. ACh diffuses across synaptic cleft and binds to ACh receptors, generating an end plate potential (EPP)
    • If the EPP > threshold for generating an AP, all-or-none depolarization of the muscle membrane occurs: threshold around 40-60-mV
    • Propagated AP penetrates T tubule system, triggering muscle fiber contraction
    • EPP terminated via hydrolysis of ACh by AChE within a few sec
  6. The Safety Factor
    • Normally EPP is 4-5 x the threshold for AP generation: The excess receptor activation is termed the safety factor
    • EPP amplitude is dependent on: !
    • presynaptically on number of quanta released
    • postsynaptically on number and sensitivity of ACh receptors available for binding
  7. Safety factor reduced by
    • increased temperature
    • exercise
    • ischemia
  8. Myasthenia Gravis
    • Incidence: 1-9 million
    • F > M (7:3 in young age group, 1:1 in older)
    • F peak at ages 20-24 and 70-74 years
    • M peak at ages 30-34 and 70-74 years
    • Prevalence: 25-142 per million
    • 10% cases present in childhood (juvenile myasthenia)
  9. Myasthenia Gravis: Pathophysiology
    • In 85% patients with generalized MG and 50% patients with ocular MG, antibodies directed against ACh receptors:
    • binding antibodies
    • blocking antibodies
    • modulating antibodies
    • MuSK antibodies: and other antibodies
  10. Myasthenia Gravis: pathophysiology
    • in the case of antibodies to ACh receptors, damage to the NMJ occurs from:
    • accelerated degradation of ACh receptors
    • blocking active sites on ACh receptors
    • Damaging ACh receptors with the aid of complement
  11. Thymic pathology in MG
    • 40-70-% of patients with autoimmune MG have evidence of thymic hyperplasia
    • 10-15% of patients with autoimmune MG have underlying thymoma
  12. Presenting symptoms of MG
    • Ocular: ptosis, diplopia
    • Bulbar: dysphagia, dysarthria, dyrphonia
    • Generalized: Neck, limb weakness
    • Distinctive feature is fluctuating nature of symptoms, producing a dynamic rather than static disorder
  13. Ocular symptoms are first manifestation
    • in the vast majority of patients (90%)
    • Generalization ultimately occurs in two-thirds of patients with OMG, the majority within 2 years
    • In most patients, the severity of disease lessens with time and remissions are possible
  14. Physical exam in Myesthenia Gravis
    • Ocular signs: ptosis, diplopia on testing o EOM, weakness of eye closure, over-contraction of frontalis
    • Bulbar signs: jaw weakness, facial diplegia, palatal weakness, tongue weakness
  15. Respiratory signs: MG
    • Respiratory rate
    • use of accessory muscles
    • ease of speech
  16. MG Dx workup
    • Antibody testing: ACh R antibodies in 85% GMG , 50% OMG; MuSK antibodies in roughly 10% GMG, rare OMG
    • Thyroid function studies
    • EMG and Nerve Conduction Studies
    • Evaluation for thymic pathology: CT or MRI of the chest
    • Tensilon test - no longer commercially available
    • Ice pack test
  17. MG repetetive nerve testing stimulation
    the peak of the strength decreases because there is muscle fatigue
  18. Treatment of Myesthenia Gravis
    • Ocular vs. Generalized
    • Anti-acetylcholinesterase Rx
    • Prednisone
    • Steroid-sparing agents
    • IVIg
    • PE
  19. Treatment of ocular MG
    • Initially, pyridostigmine - most commonly used
    • If Sx refractory to pyridostigmine and impacting QOL, prednisone
  20. Anti-acetylcholinesterase medications: pyridostigmine - side effects
    • Nausea, vomiting
    • Abdominal cramping
    • Diarrhea
    • Sialorrhea (drooling)
    • Bradycardia
    • Encephalopathy (rare)
    • Cholinergic crisis (rare)
  21. Treatment of generalized Myesthenia Gravis
    Initial treatment with pyridostigmine and prednisone
  22. Side effects of prednisone
    • increased susceptibility to infection
    • impaired glucose tolerance
    • hypertension
    • Glaucoma
    • Cataracts
    • Osteoporosis
    • Aseptic necrosis of the femoral neck
    • Myopathy
    • Psychosis/mania
    • insomnia
    • dyspepsia
    • Weight gain/hirsutism
  23. Azathioprine (Imuran) also side effects
    • Purine analog well-established efficacy in MG
    • Must check for TPMT mutation prior to initiation of treatment
    • Flu-like reaction (12%)
    • Myelosuppression
    • Hepatotoxicity
    • Pancreatitis
    • teratogenicity
    • risk of infection and malignancy (with prolonged use)
  24. MG treatment
    • Mycophenylate mofetil (CellCept)
    • Cyclosporine
    • Cyclophosphamide
    • IVIg: no standard dose in MG, but 2g/kg/treatment typically given
    • Plasmapharesis - often used in crisis or pre-operatively
  25. Thymectomy in MG
    • indicated in patients with thymoma
    • unclearbenefit in patients with thymic hyperplasia (maybe young & healthy adults)
    • Benefit may be delayed for months-years
  26. Myasthenic Crisis
    • Strictly defined as respiratory failure due to myasthenia gravis, though impending respiratory failure also qualifies
    • occurs more commonly within 3 years initial diagnosis of MG
  27. Myasthenic Crisis Causes
    infection, illness, surgery, trauma, stress, medications
  28. Myasthenic Crisis Dx
    • Largely based on history and exam
    • assessment of pulmonary function: NIF and FVC
  29. Myasthenic Crisis Treatment
    • Protection of airway: endotracheal intubation and ventilation versus noninvasive positive pressure ventilation; signs of impending respiratory failure
    • Directed treatment toward inciting event if identifiable (e.g. infection)
    • Prudent to hold anti-acetylcholinesterase Rx
    • Plasmapheresis
  30. Congenital Myasthenic Syndromes
    • Presynaptic dysorders
    • Synaptic dysorders
    • postsynaptic disorders
  31. Lambert Eaton Myesthenic Syndrome (LEMS) - rare: presentation
    • typically complaints of weakness and easy fatigability, predominantly of proximal lower extremities
    • ** oculobulbar symptoms less common than in MG
    • Cholinergic dysautonomia
  32. LEMS Exam Findings
    • Sings of cholinergic dysautonomia
    • Proximal muscle weakness,, improved with repetitive testing (facilitation)
    • Hyporeflexia, improved with facilitation
  33. LEMS and malignancy
    • roughly two-thirds of cases associated with underlying malignancy
    • most common underlying malignancy is SCLC (90%); others include lymphoproliferative disorders, breast, ovarian, and pancreatic cancer)
  34. LEMS Dx work-up
    • Antibody testing
    • NCS/EMG
    • Evaluation for malignancy - CT torso
  35. Treatment of LEMS
    • of malignancy - patients may improve
    • Anti-acetlcholinesterase drugs may produce a modest effect (variable)
    • Immunosuppression?
  36. Botulism
    • Caused by toxin of Clostridium botulinum
    • Gram +'ve, rod-shaped, obligate anaerobe
    • A, B, E strains of toxin most common
    • Can be acquired via several routes: wound, foodborne, infantile, hidden (suspected GI), inhalational
  37. Botulism: pathophysiology
    Neurotoxins produced by C botulinum: degrade proteins necessary fo docking and fusion of ACh vesicles to the synaptic membrane, thereby preventing release into the synaptic cleft
  38. Botulism Presentation
    • Neurologic: dysphagia, xerostomia, diplopia, dysarthria begin acutely and progress over 12-36 hours with rostral to caudal progression of weakness eventually involving limbs and/or respiratory muscles
    • Gastrointestinal: Nausea, vomiting, diarrhea followed by constipation, abdomen cramps
    • Anxiety
  39. Botulism Exam
    • Ptosis, opthalmoplegia, facial diplegia, palatal and tongue weakness: often very dilated pupils
    • limb weakness and hypo- to areflexia
    • evaluation of respiratory function
    • signs of dysautonomia: e.g. poorly reactive pupillary light response, bradycardia
  40. Botulism Differential Diagnosis
    • Myasthenia
    • Guillain-Barre syndrome
    • Tick paralysis
    • Poliomyelitis
    • LEMS
    • Heavy metal intoxication
    • Stroke
  41. Botulism Dx workup
    Toxin: serum in foodborne; stool in infantile; wound scrapings in wound
  42. Botulism Treatment
    • Most patients require hospitalization for 1 to 3 months for supportive care
    • Mortality rate ~5%
    • Supportive care: respiratory monitoring, intubation as necessary gastrointestinal symptoms
    • Anti-toxin: equine serum trivalent botulism antitoxin; early treatment
    • Antibiotics: unproven but often given for wound botulism
  43. Other causes of Neuromuscular Junction Dysfunction
    • Drug-induced MG (penicillamine, amiodarone)
    • aminoglycoside antibiotics
    • Hypermagnesemia
    • envenomations (various snakes, scorpions, spiders, cobras, kraits)
    • Certain forms of tick paralysis
    • Agents designed for chemical warfare
    • Prolonged NM blockade (curare-like agents in those critically ill)

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