Exam 1: MG Flashcards
(27 cards)
Symptoms of MG
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
MG Rates of diagnosis
200-400 million
underdiagnosed
more women
2nd-3rd decade in women, 7th-8th decade in men
Neonatal myasthenia
fetus acquires antibodies from afflicted moth, symptoms subside 2-3 month after birth
History of MG
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
MG: reduced safety factor, no longer release as much Ach, so can’t get to threshold
what restores transmission?
AchE inhibitor (neostigmine)
oMG:
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
Clinical presentation of MG
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.
Edrophonium test
administration of fast acting acetcholinestase inhibitor
Temporarily relief of symptoms
Nerve conduction studies and/or single fiber electromyography
in MG, nerves and muscles will not perform well under repeated stimulation
Course of disease and progression
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
Structure of neuromuscular junction
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
Effector mechanisms of anti-AChR abs: MAC
Abs activate the complement cascade, forming MAC (membrane attack complex).
Destruction of motor end-plate morphology renders synaptic connections ineffective.
Effector mechanisms : antigenic modulation
cross-linking antigens accelerate endocytosis and degradation
Effector Mechanisms; Functional block of AChR
Abs acting as antagonist through competitive binding
Pathophysiology of MG @ NMJ
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.
Cytokine network and cells involved in MG
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
Diagnostic algorithm for MG.
So we got muscle weakness
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
Thymus in MG
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
Treatment: is prognosis good?
Yes, severity max, then improve with treatment
Treatment: Cholinesterase inhibitors
reduce Ach breakdown; transmitter accumulates @ NMJ
Treatment: Thymectomy
improvement 2-5 years after surgery, best results seen in young patients
Treatment: Corticosteroids
improvement/complete relief in 70% of patients (prednisone)
Treatment: Immunosuppressant drugs
especially for patients who don’t respond to steroids
azathioprine/cyclosporine- used for organ transplant
Treatment: plasma exchange
short-term intervention for acute crisis
