Disorders of NMJ

Question 1

What occurs at the NMJ to cause muscles to contract?

Answer 1

• 1. Ca2+ influx in the pres-synaptic neuron.
• 2. Vesicles with ACh migrate to the nerve terminal, fuse and release ACh.
• 3. Ach is released from nerve ending at the NMJ => diffuses across cleft => bind to nACh-R on muscle => muscle contracts.

Question 2

How do we classify disorders of the NMJ?

Answer 2

1. Presynatic
2. Synpatic
3. Post-synaptic

Question 3

What disorders of the NMJ are presynaptic?

Answer 3

1. Lamber-Eaton Myasthenic Syndrome
2. Botulism

Question 4

What disorder of the NMJ are synaptic?

Answer 4

1. Nerve agents (Sarin, VX)

Question 5

What disorder of the NMJ are post-synpatic?

Answer 5

1. Myasthenia gravis
2. Succincycholine
3. D-penicillamine

Question 6

What is Myasthenic Gravis?

Answer 6

AI disease => defect in neuromuscular transmission due to Anti-ACh-R Ab that bind to post-synpatic nAChR on the muscle

Question 7

Which 2 HLA haplotypes are seen with high frequency in Myasthenia Gravis?

Answer 7

HLA-B8 and DR3

Question 8

Myasthenia Gravis

• Etiology
• MC affects?

Answer 8

1. Etiology
   
   1. Most cases= sporadic,
   2. But ↑ likely in those with HLA-B8 and DR3
   3. Can occur with AI disorders
2. Younger women/older men.

Question 9

Charactersitics of Myasthenia Gravis

Answer 9

1. Fluctuating weakness/heaviness - “excessive fatigability” that occurs later in the day as we use our muscles more
   
   • bc if we repeatedly use a muscle => less ACh is released => muscle fatigues
   1. MC = EOM weakness => diplopia and ptosis.
2. Other: dysarthria, dysphagia, limb and neck weakness, respiratory insuffiency.
3. Respond to cholinergic drugs :)

Question 10

What is the classifactions of Myasthenia Gravis?

Which is the MC?

Answer 10

• 1. Purely ocular (15- 20%)
• 2. Moderely severe, generalized (25%)*
• 3. Acute fulminating (15%)
• 4. Late severe (10%)

Question 11

Labs of Myathania Gravis

Answer 11

1. Anti-AChR Ab (in 80% of generalized and 55% of ocular MG)
2. MUSK Ab
3. LPR-4Ab

Question 12

EMG findings of Myathenia Gravis

Answer 12

1. Repetitive stimulation causes ↓↓↓ in response (bc as you stimulate muscle, releases less ACh)
2. ↑ jitter on a single fiber EMG

Question 13

Clinical tests for Myasthenia Gravis

Answer 13

1. Tensilon (administer edrophonium) test = rarely done
2. Check for fatiguable weakness = have open and close eye quickly => will eventually become weak => ptosis
3. Ice bag test
4. Cogans sign

Question 14

How is Tensilon test performed to diagnosis Myasthenia Gravis?

Why is it not commonly performed anymore?

Answer 14

1. Administer 10mg of edrophonium, a short-acting AChE-I
2. Within 20 seconds, ptosis should go away.
3. Problems: + parasympathetic NS => bradycardia and ventricular arrhythmia, thus, keep atropine on hand

Question 15

Ice bag test for diagnosis of Myasthenia Gravis?

Answer 15

1. Apply ice to ptotic eyelid for 2 minutes
2. Ptosis will improve
3. 2mm improvement = positive test.

Question 16

Treatment for Myasthenia Gravis

Answer 16

1. AChE- I (Mestinon) = INC amount of ACh in cleft so increase chances of binding
2. Prednisone and other immunosuppresants
3. Plasma exchange/IVig: generally for patients in crisis or before going under surgery to avoid crisis
4. Thymectomy (optional)

Question 17

What is tx for Myasthenia Gravis pt’s in crisis or before surgery to avoid crisis?

Answer 17

IVIg / plasma exchange

Question 18

Which drug can cause a disorder identical to Myasthenia Gravis?

Answer 18

D-penicillamine

Question 19

Name a few drugs that can worsen or unmask Myasthenia Gravis?

Answer 19

1. NM blockers (succinylcholine)
2. Too much AChE-I
3. High doses of corticosteroids or ACTH

Question 20

What are 2 complication of Myasthenia Gravis?

Differentiate the 2.

Answer 20

1. Myasthenic Crisis = rapid exacerbation of the disease that occurs spontaneously, after infection or with drugs, causing [aspiration, diffuse weakness, respiratory failure].
2. Cholinergic Crisis = rapid exacerbation of disease due to too much AChE-I meds, causing miosis, fasciculations, N/V/D, sweating/saliva, bradycardia.

Question 21

How do we differentiate whether a Myasthenia Gravis exacerbation is due to Myasthenic crisis or Cholinergic Crisis?

Answer 21

Cholingeric crisis causes miosis and/or fasciculations.

Question 22

1. Which antibodies are seen in about 40% of Myasthenia Gravis (Seronegative Myasthenia Gravis) pt’s with no detectable anti-AChR Ab’s?
2. Who is this MC in?

Answer 22

• MUSK (muscle specific tyrosine kinase) Ab’s
• MC in women

Question 23

How does the treatment of Seronegative Myasthenia Gravis differ from regulat?

Answer 23

• Poor response to AChE-I or thymetctomy
• Best = PLEX, IVIg, rituximab.

Question 24

What is Lambert-Eaton Myasthenic Syndrome (LEMS)?

Answer 24

AI disease where you have Ab to presynaptic VGCa2+ channels => cant relase ACh => weakness.

Question 25

What cancer is **Lambert-Eaton Myasthenic Syndrome (LEMS)** associated with?

Answer 25

**Paraneoplastic syndrome,** often associated with **small cell lung cancer.**

Question 26

**Clinical Presentation** of LAMS

Answer 26

1. **Symmetric proximal muscle weakness** (usually not severe) that gets _better with XRICSE:_ problem walking, getting out of chair, combing hair. 2. **Autnomic dysfunction:** _dry mouth (xerostomia),_ impotence 3. **Loss of DTR** 4. **Myalgias (muscle pain\*\*)** 5. Eye/throat muscles midly affected, but way worse in MG.

Question 27

**Labs** for LEMS

Answer 27

1. **Anti-VGCa2+ Ab** (in majority of pts)

Question 28

**EMG findings** for LEMS

Answer 28

1. **Low amplitude motor response** that _↑↑↑ with brief periods of XRCISE_ 2. **Rapid rates of stimulation** cause _incremental response (often \>100%)_

Question 29

Treatment of **Lambert Eaton Myasthenic Syndrome (LEMS)**

Answer 29

1. **First, look for cancer and treat** 2. **AChE-I** 3. Amifampridine 4. Immunosupression, IVIg

Question 30

How is LEMS different from MG on EMG?

Answer 30

* **MG** =\> repeated stimulation causes decrease response * **LEMS** =\> repeated stimulation increases response (bc increases ACh in cleft)