Exam 1: MG

Question 1

Symptoms of MG

Answer 1

fatigue skeletal muscle weakness, face, neck

weakness worsens with activity, improves with rest.

Facial muscles.

80% generalized over 1st year: trunk, arms, legs

ocular - just eyes

Loss of functional AChrs

Question 2

MG Rates of diagnosis

Answer 2

200-400 million
underdiagnosed
more women
2nd-3rd decade in women, 7th-8th decade in men

Question 3

Neonatal myasthenia

Answer 3

fetus acquires antibodies from afflicted moth, symptoms subside 2-3 month after birth

Question 4

History of MG

Answer 4

1934- resembles curare poison, treat with cholinesterase inhibitors

1937- mass removed from thymus improves symptoms

1959/1960- MG autoimmune

1973: rabbits immunized with AChRs develop MG symptoms, experimental autoimmune disease

2000- MUSK identified as autoantigen

Question 5

MG: reduced safety factor, no longer release as much Ach, so can’t get to threshold

what restores transmission?

Answer 5

AchE inhibitor (neostigmine)

Question 6

oMG:

Answer 6

ptosis and diplopia are initial symptoms in 2/3 patients

ptosis- dropping of 1/both eyelids
diplopia- double vision due to weakness of muscles controlling eye movements

fewer AchRs, less folds, more vulnerable

Question 7

Clinical presentation of MG

Answer 7

1-2 year delay in diagnosis

impairment of eyes/weakness WITHOUT LOSS OF TACTILE SENSITIVITY

deep tendon reflexes normal.

blood test for elevated antibodies to AchR- 80% patients
Antibodies to MuSK too

Chest radiograph and CT scan indicated to identify thymoma.

Question 8

Edrophonium test

Answer 8

administration of fast acting acetcholinestase inhibitor

Temporarily relief of symptoms

Question 9

Nerve conduction studies and/or single fiber electromyography

Answer 9

in MG, nerves and muscles will not perform well under repeated stimulation

Question 10

Course of disease and progression

Answer 10

course of disease variable but progressive

before current treatment: 1/3 improve, 1/3 stable, 1/3 die

Symptom fluctuate before stable, may see atrophic muscles

symptoms worsen by emotional upset, infection, menstrual cycle, pregnancy, hypo/hyperthyroidism

Question 11

Structure of neuromuscular junction

Answer 11

AchR structure is critical to the safety factor of the receptor

Depolarization through trough v-gated Na+

Argin/LRP4/MUSK/rapsyn- needed to anchor AchRs to NMJ structure.

1) Agrin binds to LRP4 and MUSK
2) Musk activated
3) clustering AChRS

Question 12

Effector mechanisms of anti-AChR abs: MAC

Answer 12

Abs activate the complement cascade, forming MAC (membrane attack complex).

Destruction of motor end-plate morphology renders synaptic connections ineffective.

Question 13

Effector mechanisms : antigenic modulation

Answer 13

cross-linking antigens accelerate endocytosis and degradation

Question 14

Effector Mechanisms; Functional block of AChR

Answer 14

Abs acting as antagonist through competitive binding

Question 15

Pathophysiology of MG @ NMJ

Answer 15

Reduced density of AChR
Blocked ACh binding

increased AChR internalization and degradation

MAC formation and damage of postsynaptic membrane

AChR antibodies: activate complement damaging the postsynaptic membrane through MAC

Antibodies crosslink AChRs, causing internalization/degradation.
Antibodies can directly block Ach binding site.
Anti-MUSk antibodies prevent interaction of musk and LRP4, reducing AChR.

Antibodies to COlQ, titin, ryanodine receptors, cortactin and Kv1.4 also found.

Question 16

Cytokine network and cells involved in MG

Answer 16

TH1= proinflammatory, activate complement
MG patients have elevated IL-18 levels, increase TH1 cells.

APC cells release IL-18 promotes TH1 growth and NR cells

NK release iFN-4, sentensizes TH1 cells

T-cells activate B cells, which make antibodies

Question 17

Diagnostic algorithm for MG.

So we got muscle weakness

Answer 17

assays for anti-AChR and anti-MuSK (Seropositive = +)

EMG repetitive stimulation (decreased = +)

Single fibre EMG (increase jitter = +)

Acetylcholinesterase inhibitor test (clinical improvement) –> MG probable

Purely ocular MG AND asymmetrical fluctuating ptosis/double vision –> MG probable

Finally, if likely, or for sure, do CT/MRI for thymus

Question 18

Thymus in MG

Answer 18

contains myoid cells expression AchR antigens and T-cells.

Theory: breakdown in self-tolerance results in AChR antibody production.

Primary cause or 2nday effect?

10% MG patients have thymic tumor (usually benign)
70% have hyperplastic change indicative of immune response

Question 19

Treatment: is prognosis good?

Answer 19

Yes, severity max, then improve with treatment

Question 20

Treatment: Cholinesterase inhibitors

Answer 20

reduce Ach breakdown; transmitter accumulates @ NMJ

Question 21

Treatment: Thymectomy

Answer 21

improvement 2-5 years after surgery, best results seen in young patients

Question 22

Treatment: Corticosteroids

Answer 22

improvement/complete relief in 70% of patients (prednisone)

Question 23

Treatment: Immunosuppressant drugs

Answer 23

especially for patients who don’t respond to steroids

azathioprine/cyclosporine- used for organ transplant

Question 24

Treatment: plasma exchange

Answer 24

short-term intervention for acute crisis

Question 25

Treatment: physical therapy

Answer 25

provides lifestyle adjustment or coping strategies

Question 26

Chronic MG (diagnosis confirmed)

Answer 26

acetylcholinesterase inhibitor and thymectomy

prednisolone and azathioprine

replace azathioprine with another immunosuppressive drug

Question 27

Acute MG exacerbations

Answer 27

intensive care, IVIg or plasma exchange, treatment of infection and other precipitating events

plasma exchange or IVIg, glucocorticoids in megadose, intensive care