Disorders of the Nicotinic NMJ

Question 1

two key elements of the presynaptic region of the nicotinic NMJ

Answer 1

1. voltage gated Ca++ channels embedded in the membrane (VGCC)
2. synaptic vesicles containing ACh (5-10 thousand molecules of ACh (quanta) in each vesicle)

Question 2

two key elements of the postsynaptic region of the nicotinic NMJ

Answer 2

1. nicotinic acetylcholine receptors (nAChR) (5 subunits surrounding an ion channel)
2. AChE

^both embedded in junctional folds

Question 3

MIR and role in myasthenia gravis

Answer 3

main immunogenic region
- extracellular portion of AChR sticking into cleft

-Abs bind here, activate complement cascade, which leads to destruction of target of Ab (destruction of AchR and surrounding membrane)

Question 4

all cases of myasthenia gravis are ___ mediated

Answer 4

all cases of myasthenia gravis are antibody mediated

Question 5

Is myasthenia gravis genetic or AI disorder?

Answer 5

Not a genetic disorder but a genetic disorder to AI disorders can lead to MG

Question 6

10+% of pts w/ MG have a tumor of the …

Answer 6

thymus gland (thymoma)

a true paraneoplastic disorder

Question 7

MG is a _____ muscle disorder that causes muscle _____

Answer 7

MG is a STRIATED muscle disorder that causes muscle WEAKNESS

Question 8

Which type of weakness usually presents w/ MG?

Answer 8

Fatigable weakness (development of weakness of muscles that occurs WITH use).

involves ocular muscles, oropharyngeal muscles and less commonly, diaphragm and proximal limb muscles.

Question 9

Ocular m. involvement w/ MG consists of

Answer 9

Diplopia (double vision)
ptosis (drooping eyelids)
ophthalmoplegia (weak eye movement)

Question 10

Oropharyngeal m. involvement w/ MG consists of

Answer 10

• Fatigable dysarthria (slurred speech)
• dysphagia (difficulty swallowing)
• difficulty chewing/closing jaw
• nasal regurgitation
• dysphagia/choking

Question 11

Mostly all MG pts develop ____ m. abnormalities

Answer 11

Mostly all MG pts develop OCULAR m. abnormalities

~80%

Question 12

MG examination features

Answer 12

1. fatigable ptosis/opthalmoplegia
2. fatigable limb weakness
3. normal sensory exam
4. no CNS signs

Question 13

Tenslion test

Answer 13

short-acting AchE inhibitor will relieve symptoms if myasthenic (+test)

Question 14

repetitive n. stimulation to test for MG

Answer 14

give repeated shocks to m.

m. responds w/ depolarization that we measure

consecutive shots fatigue m. fibers –> see decrement in amplitude bc m. fibers drop out due to lack of ACh

Question 15

EVERY PT WITH DX OF MG NEEDS A ____ TO LOOK FOR ____

Answer 15

EVERY PT WITH DX OF MG NEEDS A [CHEST CT] TO LOOK FOR [A THYMOMA]

even just a little ptosis is enough to qualify imaging of the chest

Question 16

MG meds - general types

Answer 16

• AChase inhibitors (symptomatic drug only)
• immunosuppressants (reduce Abs)
• complement blockades (for pts who fail conventional tx)

Question 17

Most commonly used immune suppression of myasthenia

Answer 17

prednisone

Question 18

role of thymectomy in MG

Answer 18

thymoma –> resection often curative for tumor (not curative for MG, but beneficial)

Reasoning…
normal thymus gland –> site of AI activation, actual muscle receptors that look like ACh receptors in gland.

removal will reduce immune activity, but still need immunosuppressants.

Question 19

Lambert Eaton Myastehic Syndrome: prototypic ___-synaptic disorder

Answer 19

Lambert Eaton Myastehic Syndrome: prototypic PRE-synaptic disorder

Question 20

Myasthenia Gravis: prototypic ___-synaptic disorder

Answer 20

Myasthenia Gravis: prototypic POST-synaptic disorder

Question 21

LEMS pathophysiology

Answer 21

AutoAbs against presynaptic voltage-gated Ca2+ channels (VGCCs)

–> reduced Ca++ influx into presynaptic terminal during AP

–> reduced ACh release

–> reduced safety factor for PSM depolarization

–> failure to fuse and release Ach vesicles into the NMJ

–> muscle weakness

Question 22

About half LEMS cases are associated w/ ______

Answer 22

small cell lung cancers (SCLC) producing cross-reactive antibodies (a true paraneoplastic disorder)

(rest of the cases are associated w/ other AI diseases)

Question 23

LEMS clinical features

Answer 23

• slowly progressive proximal weakness (shoulders/hips)
• autonomic dysfunction (dry mouth)
• cranial nerve dysfunction (less severe than myasthenia gravis; ptosis, ophthalmoplegia)
• weakness can IMPROVE w/ REPETITION

Question 24

Is LEMS weakness similar to MG?

Answer 24

NO

MG –> fatigable weakness

LEMS –> slowly progressive proximal weakness, no fluctuations like MG

Question 25

LEMS diagnostic testing

Answer 25

• VGCC Ab test (variable sensitivity, good specificity)

- repetitive n. stimulation and single fiber EMG

Question 26

MG diagnostic work-up

Answer 26

• nicotinic AChR Abs
• tensilon test
• repetitive n. conduction studies
• single fiber EMG
• chest Ct/MRI

Question 27

Why does weakness seen w/ LEMS improve w/ repetition?

Answer 27

keep stimulating n. –> pushing more and more Ca++ into presynaptic terminal –> more Ach –> more muscle contraction

Question 28

repetitive n. stimulation to test for LEMS

Answer 28

as you stimulate nerve, amp is low –> but as you stimulate more and more Ca++ pushed into synaptic terminal

amplitude starts tiny, then gets huge –> called an INCREMENT (diagnostic for LEMS)

Question 29

LEMS tx

Answer 29

• vigorous tumor search, especially lung (chest CT, MRI.)
• ^ repeat 3 mo. if no tumor ne found
• symptomatic tx w/ 3,4 DAP (Firdapase)
• immunosuppressives (prednisone)

Question 30

nicotinic AChR role in striated muscle contraction

Answer 30

when 2 ACh binding sites on receptor are filled –> a conformational change in the receptor –> Na+ flows down gradient, K+ out –> local depolarization of muscle membrane potential –> contraction