Neuromuscular Junction (NMJ) Disorders

Question 1

What are the steps of normal neuromuscular transmission?

Answer 1

1. AP depolarizes motor nerve terminal
2. Ca influx facilitates release of ACh
3. ACh bins at specific sarcolemmal nicotinic AChR
4. if enough AChR is bound, end plate depolaries (EPP) and EPP exceeds threshold for a single muscler fiber to contract
5. co-activation of many muscle fibers causes muscles to contract
6. AChE limits action of ACh
7. slight decrease in ACh release with exercise is INsignificant, since more than enough ACh is normally released (**“safety factor”)

–Achetycholinesterase is necessary for regulation

Question 2

What are the categories of NMJ disorders and examples for each?

Answer 2

1. POST-synaptic: **myasthenia gravis (immune target is nAChR)
2. PRE-synaptic:
   
   1. Lambert-Eaton myasethenic syndrome (LEMS)
   2. botulism (exotoxin inhibits ACh release)
3. Diverse inborn errors in NMJ: congenital myasthenic syndromes (rare)

Question 3

(POSTsynaptic) MG-Epidemiology and CP

Answer 3

• begins at ANY age
• _*ocular* MG (10-20%)_
  
  • ptosis + diplopia=only symptoms after 2-3 yrs
  • sensation, cognition alright, weakness will be main issue
• generalized MG (80-90%)
  
  • (ptosis + diplopia) –and– dysarthria (difficult/unclear articulation of speech that is otherwise linguistically nml), dysphagia; respiratory, facial, neck and limb weakness
• preserved sensation and reflexes
• symptoms severity varies pt to pt, remission may occur
• fatigure occurs with certain activities
• [*diplopia from dysconjugate right lateral gaze; dbl vision–getting 2 views from the different eyes; they arent lined up, wont get same image on same spot of retina]
• [*bilat ptosis with compensatory contraction of frontalis muscle]

Question 4

the role of the NMJ in MG

Answer 4

• Ab to AChR (from B-cells heped by T-cells) block receptors and increase degradation and turnover (more so than can be accomodated/counteracted by the body)
• loss of functional AChR leads to weakness
• myasthenic fatigue occurs when the normally mild reduction of ACh released with exercise leads to a critical loss of end plate, and hence muscle fiber, depolarization.
• general:
  
  • APC (macrophages and DC in spleen, LN, thymus) take up AChR
  • present it to certain T-cells which recognize AChR and interact with B-cells, stimulating them to produce Ab to AChR
• 3 steps:
  
  1. complement-mediated lysis of endplate region
  2. accelerated degradation of AChR (cross-linking)
  3. blockade of AChR
• EM: motor nerve terminal at top, jxn; folds of muscle membrane below (folds are LESS deep with MG)

Question 5

MG-Safety Factor

Answer 5

• endplate potential (EPP) amplitude is reduced in MG
• reduced EPP narrows the safety factor of neuromuscular transmission
• with repeated stimulations the EPP amplitude falls below threshold for muscle fiber activation–neuromuscular transmission failure
• when a critical number of EPPs fail, a decremental response is seen on repetitive nerve stimulation studies

Question 6

Diagnosis of MG

Answer 6

• typical clinical features
• positive tensilon-edrophonium test
  
  • IV injection of short-acting AChE inhibitor-can completely reverse pt’s ptosis (momentarily)
• EMG evidence of abnml NMJ tranmission
  
  • repetitive nerve stimulation, single fiber jitter tests
• elevated serum Ab titer to AChR
  
  • most specific test of all!!
  • in 80-90& generalized, 50% ocular MG

Question 7

Treatment of MG

Answer 7

• Anticholinesterase drugs
  
  • inhibit AChE, enhancing effect of released ACh
  • improve symptoms, not autoimmune path (NO interaction with immune system)
  • monitor closely, high doses may produce a cholinergic crisis
    
    • weakness, swetiness, salivation, diarrhea, excessive urination
• Thymectomy
  
  • contains AChR-like material, where autoimmune response initiated?
  • HYPERplastic thymus or thymoma (rarer) occur in MG
• immunosuppressant drugs (CORTICOSTEROIDs)
• IVIG (intravenous immunoglobulin) or plasmapheresis

Question 8

Immuno(suppressive)therapy for MG

Answer 8

• thymectomy
• corticosteroids
• azathioprine or mycophenolate mofetil
• cyclosporine
• other immunosuppressants
• transient, but potent “quick fixes”
  
  • plasmapheresis or IV immunoglobulin (IVIG)

>>if effective, can shift the balance closer to the nml state

• autoimmune blocking and destruction of AChR may overcome resynthesis and repair
• effective immunosuppressive therapy can shift the balance closer to the nml state

Question 9

LEMS

A. CP

B. Diagnosis

C. Tx

Answer 9

A. CP

• fatigable weakness of proximal limbs, trunk–mimics a myopathy
• exertion briefly improves power and hyporeflexia
• autonomic symptoms (dry mouth, orthostasis)
• autoimmune attack vs. presynaptic Ca channels, often related to small cell lung cancer

B. diagnosis by nerve stimulation tests, EMG; occasional detection of specific Ab to voltage gated Ca2+ channel

C. Tx

• find and treat any underlying cancer which will improve neurological symptoms
• drugs which enhance ACh release:
  
  • guanidine
  • 3,4-diaminopyridine
• immunosuppressive therapy
  
  • with suboptimal success…

Question 10

Bot

Answer 10

• canned food
• bind to presynpatic n and inhibits the release of Ach by LMN and PS
• early: eyes (diplopia, ptosis, pupillary paraysis)
• late: dyspahgia and face/limb/resp weak
• late late: respiratory paralysis