clinical approach

1. MYASTHENIA GRAVIS

2. MYASTHENIA GRAVIS
• Myasthenia gravis is an acquired autoimmune disorder of the
neuromuscular junction characterized by weakness and fatigability of
skeletal muscles
• Defect : Decrease in number of ACh receptor due to autoimmune
attack

3. PATHOLOGY
A. anti-AChRs antibodies
-Immunoglobulin G1 (IgG1) and G3 (IgG3) autoantibodies by attacking, and
complement fixation)
- Present in 90% of cases
By three distinct mechanisms:
1. Accelerated turnover of AChRs (by cross-linking and and rapid endocytosis)
2. Damage to postsynaptic muscle membrane (by Ab and complement)
3. Blockage of active site of AChRs)

5. B. Anti Muscle Specific Kinase (MuSK) receptor
- Occurs in 40-0 % of AChR Ab Seronegative Pt.
- MuSK-A protein involved in AChR clustering at NMJ
C. Low Density lipoprotein receptor related protein 4 (LPR4)
- Important for AChR clustering

7. THYMUS
• Produced IgG in MG - T cell dependent
• Abnormal thymus in 75% of AChRs ab positive (hyperplastic thymus), and
10% with Thymomas
# Muscle-like cells within the thymus (myoid cells), which express AChRs on
their surface, may serve as a source of autoantigen and trigger the
autoimmune reaction within the thymus gland.

8. SERONEGATIVE MYASTHENIA GRAVIS
• An autoimmune disorder with most of the same features as seropositive
myasthenia gravis and identical electrophysiological findings
• No detectable autoantibodies against AChR and MuSK
• Also called "double-seronegative"

9. KEY POINTS
Presynaptic Rundown -
Neurotransmitter per impulse with
repeated activity
Flattened/ simplified
post synaptic membrane
Myasthenia fatigue :
due reduced muscle fiber activation
with successive impulses

10. CLINICAL FEATURES
• Prevalence : 2-7/10000 cases
• Affects all ( Peak M: 50s-60s, F: 20s-30s with F>M)
• Neonatal myasthenia gravis – transient , due to trans-placental passage of
maternal antibodies
Clinical presentation :
Cardinal features: Weakness and Fatigability
Weakness- increases with activities/exercise
# Early – Cranial muscle involvement
Lids and extraocular muscle – ptosis, and diplopia;
Fascial muscle weakness – snarling expression on smile
Tongue weakness- nasal timbre or dysarthric “mushy” quality
Difficulty in swallowing (Aspiration)

11. • Weakness on generalization involve- limb muscles
• Limb weakness – proximal and may be asymmetric
• Generalization unlikely - If weakness remains restricted to
extraocular muscle for 3 years
• Myasthenia crisis : when weakness of respiratory muscle occur,
requiring respiratory assistance

12. DIFFERENTIAL DIAGNOSIS
• Nonautoimmune inherited myasthenic syndrome
• Drug induced myasthenia
• Lambert Eaton myasthenic syndrome
• Hyperthyroidism
• Botulism
• Intracranial mass lesions

13. DIAGNOSIS AND EVALUATION
1. Antibodies to AChR, MuSK, or lpr4
assay
• Anti-AChR radioimmunoassay:
• definite diagnosis if positive
• ~85% positive in generalized MG;
• 50% in ocular MG
• negative result does not exclude MG;
• ~40% of AChR antibody–negative
patients with generalized MG have anti-
MuSK antibodies

14. 2. Electrodiagnostic testing
• Repetitive nerve stimulation – electric shock 2-3 per second
Normal – no change in amplitude of evoked muscle action
potential
MG- rapid reduction of amplitude (by >10-15%)

15. 3. AnticholinesteraseTest
• drugs that inhibit AChE used
• Edrophonium (Rapid onset 30s, Short duaration 5 min)
• Given in two divided dose (if 1st dose insufficient, so as to reduce ADR)
• Initial IV 2 mg observe if no change, then 8mg IV
+ ve- when improvement of symptoms
-ve – the exacerbation of symptoms (Cholinergic crisis)

16. MANAGEMENT
Goal of therapy
• Symptomatic treatment (acetylcholinesterase inhibition) to increase
the amount of acetylcholine (ACh) available at the neuromuscular
junction
• Chronic immunosuppressive therapies (glucocorticoids and
nonsteroidal immunosuppressive agents) to target the underlying
immune dysregulation
• Rapid but short-acting immunomodulating treatments (therapeutic
plasma exchange and intravenous immune globulin [IVIG])

17. Very good prognosis
1. Anticholinesterase therapy
• More benefit in anti AChR MG patient than anti-MuSK MG
• Used drugs- pyridostigmine (initial 30-60 mg dose 3-4 times
a day and dose adjustment needed, Max-120 mg every 4-6
hourly in day (Adr: Diarrhea, Abdominal cramps, Salivation,
Nausea)

18. 2. Immunosuppression
• Effective in all MG pt.
• For intermediate plan (1-3 months)- Glucocorticoids, and
cyclosporine or tacrolimus
• Prednisolone given in single dose ( to minimize adr) rather in
divided doses throughout the day
• Rituximab –monoclonal ab that depletes CD20 B cells
- good response in anti-MuSK MG.

19. 3. Thymectomy
• 85% pt. experinces improvements
• Anti AChR MG respons well than atni-MuSK MG
• Thymectomy should be carried out in generalized MG in all pt with age
between puberty and 55y
4. Plasmapheresis and intravenous immunoglobin
• Indication : to produce rapid improvement to help the pt. through a difficult
period of myasthenia weakness or prior to surgery
• A course of 5 exchanges (4-5L/exchange) over 10-14 days period

21. REFERENCES
• Casper et al, Harrison’s Principles of Internal
Medicine, 19th edition.
• Up to Date, last updated: Aug 21, 2017

22. •Thank you