Pathophysiology of Muscle Disorder: MG

1. Myasthenia Gravis
Josan Legore
November 15, 2021

2. Objectives
1. To outline what is Myasthenia Gravis (MG)
2. To describe the cause of MG
3. To illustrate the signs and symptoms of MG
4. To discuss the pathophysiology of MG
5. To outline the treatment/cure of MG
6. To mention any notable people with or associated with MG

3. Myasthenia Gravis
An autoimmune disorder of neuromuscular transmission in voluntary
skeletal muscles.
AUTOIMMUNE:
Antibodies in the bloodstream
that inhibits or degrades one’s
acetylcholine (ACh) receptors.
Location:
At the postsynaptic
neuromuscular junction.
NEUROMUSCULAR
TRANSMISSION:
Inability of the neuromuscular
junction to rely sufficient
signals.
Location:
From the nerve fibers to the
muscle fibers.

4. Risk Factors
Generally observed in any age, both genders and all races.
However, most common in:
Young women below 40 years old (20-40 years old).
Older men above 40 years old (50-70 years old).
Herrmann and his colleagues (in a 1985 article) demonstrated that
MG affects more women (2/3) than men (1/3).

5. Causes of Myasthenia
Gravis (1)
Thymus plays a critical role in the
pathophysiology of MG.
 Provides T-helper cells that are
sensitized against thymic proteins that cross
react with ACh receptors.
~ 20% of MG cases may be due to
Thymomas.
Thymus is hyperplastic (enlarged) in MG
patients.
Tumour of the Thymus  Thymomas

6. Causes of Myasthenia Gravis (2)
Receptors at the muscle
surface are degraded.
Block normal muscular
transmissions.
Destruction of Nicotinic ACh
Receptors (nAChRs)

7. Signs and Symptoms of
Myasthenia Gravis

9. Signs and Symptoms of MG:
Ocular/Eye Muscle Weakness
Ptosis (Drooping
of the eyelids)
Diplopia (Double
Vision)
Difficulty maintaining
steady gaze

10. Ocular Muscle
Weakness
A Research study showed that at the genesis of
Myasthenia Gravis, the most common sign
observed was Ocular Muscle Weakness.
More than 50% of the patients (~59%)
had ocular muscle symptoms like
ptosis and diplopia.
Wirtz et al. (2002)
...“apparent external ophthalmoplegia was only
seen in patients with myasthenia gravis.”

11. Signs and Symptoms of MG:
Facial Muscle Weakness
Facial Paralysis Difficulties in Facial
Expressions

12. Signs and Symptoms of MG:
Bulbar/Throat Muscle Weakness
Dysphagia (Swallowing Difficulty) Chewing Difficulty

13. Signs and Symptoms of MG:
Bulbar/Throat Muscle Weakness
Hoarseness/Changing in
voice
Dysarthria (Speaking
Difficulty)
Breathing Difficulty Drooping of the Head

14. Bulbar Muscle
Weakness
Herrmann and his associates (in a 1985 article) characterized
facial muscle weakness particularly in the head region as:
“weakness of the neck with difficulty elevating and holding the
head erect.”
Slow repetitive nerve stimulation test, demonstrated notable
decrements in intercostal and phrenic nerve (Pradhan & Anand,
2020).
Result: Carbon dioxide retention and collapse
airway.

15. Signs and Symptoms of MG:
Limb/Arm and Leg Muscle Weakness
ARMS: Difficulties carrying or
lifting objects
LEGS: Difficulties climbing stairs,
walking, rising from seated position

16. “
Studies show that “among 70 patients with
Myasthenia Gravis and weakness of the limbs,
3 (3%) had weakness restricted to the legs and
12 (12%) to the arms (Wirtz et al. 2002).
Initially proximal then distal limb weakness may
follow.

17. Pathophysiology of
Myasthenia Gravis

19. Pathophysiology of Myasthenia Gravis
Activation of Complement-mediated cascade by Bound Antibodies
Antibodies IgG predominates
Formation of membrane attack complex (MAC)
Simplification of the end plates (flattens)
Results in:
1. Alters the morphology of the post-synaptic membrane of the neuromuscular
junction of MG patients.
2. Damage to the post-synaptic membrane

20. Pathophysiology of Myasthenia Gravis
Antibodies cross-link receptor muscles. Known as Antigen Modulation.
 receptor internalization and degradation.
Results in:
1. Rapid turnover of AChRs.
2. Reduces number of AChR molecules on the post-synaptic membrane to ACh.
3. Facilitates endocytosis (internalization) and lysosomal destruction (degradation
in the post-synaptic membrane).
4. No muscle contraction occurs.

21. Pathophysiology of Myasthenia Gravis
Antibodies block ACh binding and receptor activation
Antibodies with high affinity bind to the muscle nAChRs.
Results in:
1. in the number of receptors per end plate in the affected muscles.
2. Failure of neuromuscular transmission.
3. Little to no muscle contraction.

23. Pathophysiology of Myasthenia Gravis
Autoantibodies against Muscle-specific receptor tyrosine kinase
(MuSK)
 MuSK: vital mediator of ACHR clustering at the end of plate.
 Agrin- dependent protein on the muscle membrane.
 Binds to low-density lipoprotein receptor-related protein 4 (LRP4)
to form the MuSK complex.
Results in:
1. Inhibition of clustering of the receptors in the muscle cells.
2. Inhibition of neuromuscular transmission.

24. Normal Muscle Contraction
Weakness
of Muscles
Number of
available
ACHRs at the
postsynaptic
membrane
Simplification
of postsynaptic
folds (flattens)
Neuromuscular
transmission
(unsuccessful)
NOTE: ACh is
released
normally
No muscle
contraction
Myasthenia Gravis

25. Treatment of Myasthenia Gravis
Treatment Method Mechanism of Action Function Adverse Effect(s)
Anticholinesterase: Pyridostigmine
bromide
Neostigmine bromide
Onset: 15-30mins
Duration: 3-4 hours
Dose: 30-60mg 3x daily
1. Improve muscular
contraction and
strength.
2. Enables greater
amounts of ACh to
accumulate in the
synaptic space at the
neuromuscular
junction.
3. Inhibit the immune-
mediated degradation
of AChRs.
Cholinergic crises
(paradoxical increase in
muscle weakness due to
an excess of ACh).
Diarrhoea (loose stools)
Corticosteroids:
Prednisone
Onset: 2-4 weeks
Duration: slow, take
weeks
Dose: 15-25mg/day
(single dose)
1. Suppresses the
function of the
immune system.
2. Limits antibody
production.
Loss of bone density,
fluid retention,
hyperglycaemia,
hypertension or life-
threatening if bulbar
symptoms are persistent.

26. Treatment of Myasthenia Gravis
Treatment Method Mechanism of Action Function Adverse Effects
Immunosuppressants:
Azathioprine
Onset: 12-18 months
Duration: may take weeks
Dose: 50mg (single
morning dose)
Suppress the immune
system by reducing the
production of antibodies
Dose-related Leukopenia
and hepatotoxicity
Surgery:
Thymectomy
Onset: 6-12 months Surgical removal of the
Thymus
Rare
Plasmapheresis
(Plasma Exchange)
1 plasma volume
exchanged/procedure
Remove antibodies that
block the neuromuscular
transmission
Hypotension,
hypocalcaemia,
pneumothorax (collapsed
lungs)
Intravenous
immunoglobulin
Onset: 1-2 weeks Degrades destructive
antibodies
Headache, urticaria (hives),
nephrotoxicity

27. Notable People with Myasthenia Gravis
Aristotle Onassis Sir Laurence Oliver Actress Suzanne Rogers
American Athlete
James Carter
Hip-hop Artist
Stephen Garrett
“Static Major”

28. Fun Facts about Myasthenia Gravis
Associated with
other disorders:
It is not inherited
by dominant,
recessive or sex-
linked factors, but
it was more seen
in certain families
than the general
population
Hyperthyroidism
(Graves),
Rheumatoid
arthritis, Multiple
sclerosis,
Systemic lupus
erythematosus
Absolutely NO
CURE is observed
AS YET!

29. Difference between Myasthenia Gravis and
Lambert-Eaton Myasthenic Syndrome (LEMS)
Properties Myasthenia Gravis Lambert-Eaton Myasthenic
Syndrome (LEMS)
Age at onset Younger (20-40) Older (50s)
Occurrence of Weakness Ocular, Bulbar, Facial, Proximal
Arm and sometimes legs
Proximal leg weakness
Autonomic symptoms Absent Present
Facilitation with exercise Becomes stronger with rest Becomes stronger with activity
Neuromuscular level affected Postsynaptic membrane Presynaptic membrane
Mechanism of Action nAChR is blocked or destroyed by
antibodies
Decline in quantal release of ACh
that is blocked by VGCC
antibodies
Associated Tumour Thymoma (typically benign) Small cell lung carcinoma

30. References
Herrmann, C., Jr., et al. (1985). Myasthenia gravis- current concepts. The Western Journal of Medicine,
142(6), 797-809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1306182/
Hammer, G.D., & McPhee, S.J. (2014). Pathophysiology of disease: An introduction to clinical medicine.
McGraw-Hill Education.
Guyton, A.C., & Hall, J.E. (2011). Textbook of medical physiology. W.B. Saunders. 812-817
Pradhan, S., & Anand, S. (2020). Respiratory assessment of myasthenia gravis patients using repetitive
nerve stimulation of phrenic and intercostal nerves. Neurology India, 68(6), 1394-1399.
https://www.neurologyindia.com/article.asp?issn=0028-
3886;year=2020;volume=68;issue=6;spage=1394;epage=1399;aulast=Pradhan
Rousseff, R.T. (2021). Diagnosis of myasthenia gravis. Journal of Clinical Medicine, 1-16. DOI:
https://doi.org/10.3390/ jcm10081736
Farmakidis, C., et al. (2018). Treatment of Myasthenia Gravis. Neurologic clinics, 36(2), 311–337.
https://doi.org/10.1016/j.ncl.2018.01.011
Wirtz, P., et al. (2002). Difference in distribution of muscle weakness between myasthenia gravis and the
lambert–eaton myasthenic syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 73, 766-768.