Neuromuscular Junction (Ferguson)

Question 1

Neuromuscular diseases are conditions that involve pathology in the _______, ________, ________, ________, _______ and/or ______ in the brainstem or spinal cord

Answer 1

• Muscle
• Neuromuscular junction
• Peripheral nerves (including CN)
• Spinal nerve roots
• Nerve plexus
• Motor nerve nuclei

Question 2

Normal anatomy and physiology of the neuromuscular junction;

• releases more ACh than needed for muscle movement - becomes saturated

Question 3

What diagnosis?

• Bimodal distribution - what ages?
• Presentation can be generalized, bulbar (CN), or ocular
• Symptoms are worse at the end of the day

Answer 3

Myasthenia Gravis

• Teens - 30 (females); 50-70 (males)

Question 4

What changes can you see on EM?

Answer 4

Due to chronic inflammation - see decreased surface area, decreased # of receptors, leading to the propensity to be much weaker!

Question 5

Pathophysiology of Myasthenia Gravis:

• Blocking of the skeletal muscle _____ ____ site!
• Accelerated ______ and ______ of AChr caused by crosslinking by the IgG antibodies
• _______ - mediated lysis of the muscle end plate. This results in distortion and simplification of the muscle end plate

Answer 5

• Nicotinic ACh receptor
• internalization, degradation
• Complement

Question 6

• What is the role of the thymus in MG?
  
  • thymocytes in culture spontaneously produce anti-AChR ab
• In ACh-receptor antibody positive MG patients - 50% have ______, 10-15% have a ______

Answer 6

• Remains unclear - but it houses all the functional components to produce the immune response seen in MG
  
  • May be involved in initiation and maintenance
• 50% thymic hyperplasia
• 10-15% thymic tumor

Question 7

MG has a highly variable symptomatology!!!

• Often there is a history of fluctuating weakness of extraocular, oropharyngeal, axial, limb muscles
• 2 pearls?

Fatiguing Maneuvers?

• Can you name some?

Answer 7

• “fatigable weakness” diurnal variation”
• Sustained upgaze (30-60 sec) [medial rectus most likely involved]
• Sustained abduction of arms (120 sec)
• Sustained elevation of leg while laying supine (90 sec)
• Repeated rising from chair without arm use (up to 20 sec)
• Counting out loud (watch breaths 1-50) [dysarthria, sob may be enhanced]

Question 8

What is:

• the most common antibody in MG
  
  • Found in 80-85% of myasthenics
  • only presents in 50% of isolated ocular cases
• Low false positive number (solid specificity)
• “GOLD STANDARD” lab analysis

Answer 8

Anti-ACh receptor antibody

Question 9

What is:

• NMJ protein that plays a role in clustering ACh receptors
• Typically seen in generalized MG
  
  • rarely seen in isolater ocular MG
  • presents in up to 40% of ACh receptor binding antibody negative patients

Answer 9

Anti-muscle specific tyrosine kinase

Question 10

What is:

• First antibody discovered in MG
• Very highly associated with thymoma
  
  • Present in 75-80% of those with the tumor
  • also present in non-tumor settings
• Study is utilized most often in 2 settings:
  
  • Young, newly diagnosed patients as adjunct to help detect thymoma
  • Older patients with mild disease, where this could be the only abnormality

Answer 10

Anti-striated muscle antibody

Question 11

What electrodiagnostic test:

• The sensitivity for diagnosing MG ranges from 53% to 100% in generalized MG, and 10-17% for ocular MG
• If this test is normal and a high suscpicion for an NMJ disorder exists, SFEMG of at least one symptomatic muscle should be performed

Answer 11

Repetitive nerve stimulation

Question 12

What test:

• ACh-esterase inhibitor that can be administered via IV at bedside
  
  • Advantages: assess for improvement in ptosis, weakness
    
    • Rapid onset: 30 sec
    • Short duration of effect: 5-10 min
    • Sensitivity: 71-95% for generalized MG
  • Drawbacks:
    
    • must blind physician to drug vs placebo
    • side effects: bradycardia, hypotension
    • not reliable in anti-MuSK MG
    • not very specific to the diagnosis of MG

Answer 12

Edrophonium (Tensilon) Test

Question 13

Symptomatic treatment for MG:

• A cholinesterase inhibitor
• Increases the size and length of end plate potential
• Onset is within 30-45 minutes with loss of effect between 3-6 hours
  
  • SE: stomach cramps, diarrhea, sweating, increased bronchial and nasal secretions, bradycardia, N/V –> decrease dose to minimize side effects

Answer 13

Pyridostigmine (Mestinon)

Question 14

What short term immunosuppressant treatment of MG:

• temporarily reduces the levels of circulating ab
  
  • most patients see symptomatic improvement in days
  • typical course is 3-6 scheduled every other day
  • not every day - DEPLETES CLOTTING FACTORS
  • Often used for exacerbations, or employed regularly scheduled basis in multidrug resistant patients

Answer 14

Plasma exchange {PLEX}

Question 15

What short term immunosuppressant therapy for MG:

• Comparable to PLEX
• Mechanism of action: unclear- neutralizing vs. down regulation
• symptoms improve within days and effects last between 4-8 weeks
• Dosed at 2 g/kg divided over 2-5 days
• Like PLEX, it is used in exacerbations and in resistant cases

Answer 15

IV immunoglobulin

Question 16

Long term immune-directed therapies for MG:

A: One absolute indication - presence of thymoma; not emergent

• Beneficial for patients younger than 50 years old

B: Short term Drug?

C: Long term Drugs? (for life)

Answer 16

A. Thymectomy

B: Corticosteroids

C. Chemo - azathioprine, mycophenolate

Question 17

Diagnosis?

• Approximate incidence: rare
• M:F - equal! (previously 70:30)
• Strong association with small cell lung cancer - found at least 3% of SCLC patients
• Slightly more than 1/2 of patients with this have an identifiable malignancy
• Age of onset is typically mid to late adulthood
• Non SCLC is typically found in younger females who have other autoimmune diseases

Answer 17

Lambert Eaton Myasthenic Syndrome

Question 18

What is the pathophysiology of Lambert eaton syndrome?

• AB made in response to an antigen that SCLC expresses
• Cross links multiple channels - making them ineffective by disrupting their proper positioning and function

Decreased influx of _____ leads to decreased ____

• Less binding to receptors - decreased _______
• Can result in failed transmission and low CMAP

Answer 18

IgG ab binding to voltage gated Ca channels in the presynaptic neuron

Calcium, acetylcholine

• end plate potential

Question 19

Presentation of Lambert eaton:

• No history of ____ necessary
• Slowly progressive _______ weakness (ache or tenderness)
• ____ and _____ symptoms typically very mild
• Taste?
• Will have weakness when on what type of medication?
• Prolonged paralysis following paralytic drug given prior to intubation

Answer 19

• cancer
• proximal leg or arm
• bulbar, respiratory
• Dry mouth, metallic taste
• Calcium channel blockers

Question 20

Approximately 3% of all SCLC patients have ____

• May precede diagnosis by 9 months - up to 2 years, but rare
• Smoking history and age > 50 are strong indicators that there is cancer present

PE:

• Proximal weakness with improves with exercise
• Minimal bulbar findings - occasionally, ptosis, blurred vision, difficulty chewing, dysphagia, dysarthria
• Dry eyes, dry mouth frequently reported
• Reduced/absent DTR’s; normal sensory exam

Answer 20

Lambert Eaton Myasthenic syndrome

Question 21

How is LEMS diagnosed?

• • look for VGCC antibody
• • repetitive stimulation: 3 hz, 30-50 hz.

Answer 21

• Serum testing
• Electrodiagnostic testing

Question 22

FYI: see chart

Treatment for LEMS - symptomatic and immunosuppressive treatments similar to MG, just less effective

• No role for thymectomy, need emergent tx with PLEX and IVIg

Question 23