Neuromuscular Junction.txt

• 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

• Space between nerve terminal and depression in the postsynaptic membrane into which the terminal fits
• Site of hydrolysis of ACh by acetylcholinesterase (AChE)

• 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

• 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

• 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

• 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

• increased temperature
• exercise
• ischemia

• 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)

• 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

• 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

• 40-70-% of patients with autoimmune MG have evidence of thymic hyperplasia
• 10-15% of patients with autoimmune MG have underlying thymoma

• 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

• 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

• 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

• Respiratory rate
• use of accessory muscles
• ease of speech

• 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

the peak of the strength decreases because there is muscle fatigue

• Ocular vs. Generalized
• Anti-acetylcholinesterase Rx
• Prednisone
• Steroid-sparing agents
• IVIg
• PE

• Initially, pyridostigmine - most commonly used
• If Sx refractory to pyridostigmine and impacting QOL, prednisone

• Nausea, vomiting
• Abdominal cramping
• Diarrhea
• Sialorrhea (drooling)
• Bradycardia
• Encephalopathy (rare)
• Cholinergic crisis (rare)

Initial treatment with pyridostigmine and 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

• 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)

• 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

• indicated in patients with thymoma
• unclearbenefit in patients with thymic hyperplasia (maybe young & healthy adults)
• Benefit may be delayed for months-years

• 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

infection, illness, surgery, trauma, stress, medications

• Largely based on history and exam
• assessment of pulmonary function: NIF and FVC

• 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

• Presynaptic dysorders
• Synaptic dysorders
• postsynaptic disorders

• typically complaints of weakness and easy fatigability, predominantly of proximal lower extremities
• ** oculobulbar symptoms less common than in MG
• Cholinergic dysautonomia

• Sings of cholinergic dysautonomia
• Proximal muscle weakness,, improved with repetitive testing (facilitation)
• Hyporeflexia, improved with facilitation

• 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)

• Antibody testing
• NCS/EMG
• Evaluation for malignancy - CT torso

• of malignancy - patients may improve
• Anti-acetlcholinesterase drugs may produce a modest effect (variable)
• Immunosuppression?

• 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

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

• 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

• 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

• Myasthenia
• Guillain-Barre syndrome
• Tick paralysis
• Poliomyelitis
• LEMS
• Heavy metal intoxication
• Stroke

Toxin: serum in foodborne; stool in infantile; wound scrapings in wound

• 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

• 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)