1. Myasthenia Gravis

2. Myasthenia Gravis NMJ / Endplate Chemical synapse Presynaptic membrane
Synaptic cleft
Postsynaptic membrane

3. Arrival of AP to Nerve terminal
Ca++ enters presynaptic terminal thru VGCCs.
Vesicle fuses to presynaptic membrane
Ach released to synaptic cleft within msec.
Ach bind to AchR, open pores, cations enter, resulting in an EPP
EPP reaches threshold, muscle AP is propagated.

4. Nicotinic Acetylcholine Receptor
Glycoprotein:5 subunits
Alpha ( 2 )
Beta ( 1 )
Epsilon ( 1 )
Gamma ( 1 )
Binding site of Ach
Alpha subunits
Codon
Opens channel to cations
Half-life of AchR is 8.5 days

5. Myasthenia Gravis Autoimmune disorder
Caused by antibody-mediated attack on the postsynaptic nicotinic Ach of the NMJ
Destruction of the AchR and postjunctional folds
Widening of the Synapse
Interferes with Ach binding

6. Myasthenia Gravis Prevalence (US) Annual Incidence Bimodal incidence
1/10,000 persons
Annual Incidence
2-5 per year/million
Bimodal incidence
Younger females y/o
Older males yrs
Genetics
Higher freq HLA-B8, DR3

7. Clinical Features Fluctuating Weakness Ocular muscles
Ptosis, Diplopia
Oropharyngeal Muscles
Dysphagia, dysphonia, jaw fatigue
Proximal Muscles
No sensory symptoms
No cognitive abnormalities
No incoordination
Normal reflexes

8. Pathophysiology
Immune-mediated attack against postsynaptic nicotinic receptors
Myoid cells/ other stem cells in thymus
Hyperplastic in 2/3 of patients with MG
Thymoma in 12%
May serve as autoantigens
Express surface AchR or one of its protein components

9. MGFA Clinical Classification
Grade I: Ocular MG
Ptosis and diplopia
15% never spread beyond ocular area
Grade II: Mild Generalized
Dysphonia, dysphagia, dysarthria, limb weakness
IIa extremity; IIb bulbar
Grade III: Moderate
IIIa extremity; IIIb bulbar
Grade IV: Severe
Grade V: Crisis
Respiratory failure

10. Work-up History compatible with physical examination
Tensilon test ( edrophonium )
Short acting anti-cholinesterase
Onset 30 sec, duration 5 minutes
Initial 2 mg IV
Watch for bradycardia, hypotension, arrhythmias
If no SE give 8 mg IV and observe for improvement.
Give atropine 0.5 to 1 mg IV if with SE
Ice-pack test for ptosis % sensitive.

11. Confirmatory Diagnosis
Repetitive nerve stimulation ( Jolly test )
75% sensitive
May be normal in ocular MG.
AchR antibody assay
(+) in 80-90% with generalized MG
(+) in 50% of Ocular MG
Anti-MuSK ( muscle specific tyrosine kinase )
Titers do not correlate with severity of disease.
Anti-skeletal muscle AB:
+30% gen MG, +85% MG+thymoma
SFEMG
Increased jitter
Time variation in NMJ transmission
(+) in 80% of Ocular, in 100% of generalized MG.
In 9% of MG, this may be the only abnormal Test.

12. Work-up Laboratory CXR, Chest CT r/o thymoma ( 15% MG )
ESR, ANA, RF
TSH, T4 ( hypo or hyper-T can exacerbate MG )
CBC with diff, UA, Electrolytes, Blood glucose, Renal profile.
CXR, Chest CT r/o thymoma ( 15% MG )
PPD skin test (if considering immunosuppressive trx)
PFT
Medication list review
D-penicillamine, interferon-alfa, antibiotics (aminoglycosides), Antiarrhythmics ( quinidine, procainamide ), Beta-blockers, Ca channel blockers, Phenytoin, Thyroid hormones, lithium, chlorpromazine, estrogen

14. 5-hertz Repetitive Nerve stimulation NormalsF
Threshold 15mV

15. 5-hertz RNS Abnormal
20 mV sF
16 mV
15 mV Threshold
13 mV
10mV

16. SFEMG

17. SFEMG

18. Management Symptomatic trx: anticholinesterase
Pyridostigmine (Mestinon)
Onset 30 min.
Peak 2 hrs. Lasts 3-6 hrs.
Dose: mg q 3-6 hrs. Max 120 mg q3h
IV dose is 1 per 30mg of po dose.
SE: Cholinergic
Diarrhea, N&V, sweating, hypersalivation/ secretions, Miosis, bradycardia, hypotension.

19. Management Immunotherapy: Often required Surgical treatment
Prednisone: mainstay for MG immunotherapy
15-20 mg/day, titrate up to 1mg/kg/day
Azathioprine initiated at 50 mg QD titrated to 2mg/kg/day
(Mycophenolate: 500mg BID titrated to 2-3g/day)
Cyclosporine: 5 mg/kg/day with clinical effect in 1-2 mos.
TPE
IVIG
Surgical treatment
Thymectomy indicated in thymomatous MG
Non-thymomatous MG: thymectomy is an option

20. Differential Diagnosis
Lambert-Eaton Myasthenic syndrome
Botulism
Chronic fatigue syndrome
Intracranial mass
A diagnosis of MG may give clues to other maladies
Hyperthyroidism seen in 3-8%
Autoimmune disorders
SLE, Rheumatoid arthritis

21. Questions?

22. Sir Charles Bell’s portrait of dying soldier with tetanus.
Opisthotonus and risus sardonicus

23. Cholinergic vs. Myasthenic crisis
Cholinergic crisis
Overmedication
Cholinergic Effects
Miosis
Increased salivation and secretion
Diarrhea
Cramps
Fasciculations
Myasthenic crisis
Generalized weakness
Respiratory failure