1. MG 101: The Basics
Matthew N. Meriggioli, M.D.

2. MG 101: Curriculum History of Myasthenia Gravis (MG) What goes wrong?
Problems with the immune system
Normal muscle function
Muscle function in MG
How is MG diagnosed?
How is MG treated?
Living with MG.
The Future

3. 1. History of MG Myasthenia (Greek – muscle illness)
Gravis (Latin – “grave or serious”)
First description in the 17th century
Sir Thomas Willis
“a woman who spoke freely and readily enough for a while, but after a long period of speech was not able to speak a word for one or two hours”

4. ‘On the palsy’, persons who (translated) in the morning are able to walk firmly, to fling about their Arms hither and thither, or to take up any heavy thing, before noon the stock of Spirits being spent, which had flowed into the Muscles, they are scarce able to move Hand or Foot.

5. “Treatment of myasthenia gravis with physostigmine”
In 1934, whilst still a Medical Officer at St. Alfege’s Hospital, Dr. Mary Walker discovered that a subcutaneous injection of physostigmine could (temporarily) restore muscle function in a patient with myasthenia gravis. Physostigmine was used at that time as an antidote for curare poisoning. Dr. Walker had thought that the signs and symptoms of myasthenia gravis resembled curare poisoning and that myasthenia gravis might be caused by a circulating curare-like substance --- if this were so then the signs and symptoms of myasthenia gravis would be alleviated by physostigmine. The first case of myasthenia gravis to be successfully treated with physostigmine was ‘Mrs. M.’ and the case report was published in the Lancet 2nd June 1934, pp
“Mrs. M.”
Walker MB. Lancet 1934;1:1200-1

6. First thymectomy, 1939 Alfred Blalock
21 year old woman with “cystic thymic tumor” and MG
Able to stop prostigmin
No recurrence of symptoms over 3 year follow-up period
“We wish to emphasize again the absence of conclusive proof that the improvement noted in our patient is due to removal of the tumor..”
Ann Surg 1939;110:544

7. “Guessing it Right” John A. Simpson, April 28, 1960
"Myasthenia gravis: a new hypothesis"
“…the ‘competitive-blocking’ substance must have the unusual property of persistence in the myasthenic baby for several weeks ... Where, then, are we to look for a blocking substance which must be of competitive type, transmissible through the placenta, with persistence in the child for a few weeks only, but not transmissible to another adult? If one looks at the mechanism of attachment of acetylcholine to receptor protein one is immediately reminded of the Ehrlich theory of antibody action. Let us suppose that antibody was developed against the "receptor substance" of the end-plate protein. Would not this substance have exactly the properties described?6
Immunology was still in its infancy in Multiple types of antibodies with multiple sites of action are now recognized to occur in myasthenia gravis. Many of the antibodies present in myasthenia gravis are not competitive blockers as suggested by Simpson.6 Indeed, many of the antibodies in myasthenia gravis target the acetylcholine receptor for destruction. When Simpson stated that myasthenia gravis was not transmissible to another adult, he was referring to the observation that previous attempts to reproduce the symptoms of myasthenia gravis in adults by giving them blood from a patient with myasthenia gravis had not been successful.6
Simpson JA. Myasthenia gravis: a new hypothesis. Scot Med J. 1960; 5: 419–436.

8. 2. What goes wrong?
Normal Nerve-muscle triggering (neuromuscular junction)
The neuromuscular junction in MG
Immune system abnormality

9. The Neuromuscular Junction (1)

10. The Neuromuscular Junction (2)
Nerve
Muscle

11. Why does MG cause muscle weakness?

12. MG Damages the Muscle EndplateB. NT NT

13. The Immune System and MG
The Immune System’s Job: The body’s homeland defense. Must correctly recognize potential threats and distinguish “good” from “bad”
The Neuromuscular Junction: Target of the immune system in MG

14. MG is an autoimmune disease
AChR

15. The Problem
Autoimmune Disease: occurs when the immune system loses tolerance to self tissues
Normal Immune system:
Protects
against foreign invaders

16. Why do people get autoimmune disease?
Nature Immunology (9): (2001)

17. Why do people get MG? Probably same reasons as previous slide
We don’t really know
Thymus gland

18. What is happening in the immune system in people with MG?
Anti-AChR
Abs T T B
APC T
Plasma cell
Nerve Terminal
Postsynaptic membrane
AChR
MuSK
Rapsyn
AChase
ACh
Voltage-gated
Na+ channel
Ca+ channel
Ca++
Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are caused by autoantibodies directed against the acetylcholine receptor on the postsynaptic muscle membrane.22 Anti-AChR antibodies bind to the AChR to cause receptor internalization and degradation, as well as complement-mediated lysis of the postsynaptic membrane and consequent loss of functional receptors 18

19. The Thymus Gland and the Origin of MG
Thymic
hyperplasia
AChR
In patients with thymoma, the developmental process of T-lymphocytes in thymoma is different from the one in the normal thymus. Particularly, the mechanism of removing T-lymphocytes that may react to autoantigens (including acetylcholine receptor ) may be lacking in thymoma. This may be related to the onset of myasthenia gravis in thymoma patients. We know many examples of bone marrow transplantation-related myasthenia gravis. The mechanism of bone marrow transplantation-related myasthenia gravis is similar to that in thymoma associated myasthenia gravis. Both are induced by nonspecific autoreactive lymphocytes. For those patients without thymoma, the onset of myasthenia gravis is totally unknown. These patients have abnormality in the thymus, namely, germinal centers. However, whether germinal center formation is the cause or result of myasthenia gravis is controversial. The target of the autoreactive antibody, acetylcholine receptor , may be present in the thymus. But it is not certain whether the amount of acetylcholine receptor in the thymus is sufficient to activate the developping lymphocytes in the thymus. Other theories suggest virus infection may trigger myasthenia gravis by inducing cross-reacting immunological response. This is an attractive theory. However, it lacks convincing evidence. Myasthenia gravis is not associated with any particular virus or any particular HLA type. To plan experiments that can give conclusive evidence to this problem is difficult and the progress is slow. Even if the cause of myasthenia gravis is discovered, the treatment will not change dramatically. This is because the patients are established ongoing producers of anti-acetycholine receptor antibodies. We have been unable to reduce the antibody even if we know this is the culprit. For the patients' benefit, we must find out effective ways to reduce the anti-acetycholine receptor antibody production in the patient's body. I myself have hopes in immunosuppression. Future drugs may have more powerful effect with minimal side effects. T
Thymoma
Tumor cell
AChR

20. The Thymus Gland and the Origin of MG
The thymus gland is abnormal in many MG patients
Thymectomy makes MG better (we think)
Muscle-like cells express AChR
BUT- What triggers immune attack?
Abnormal AChR?
Viral infection

21. 3. How is MG diagnosed? Clinical features Tensilon test Antibody tests
Electrical tests

22. Clinical features of MG
Muscle weakness - fluctuating
Fatigue with muscle use
Double vision, droopy eyelids, trouble swallowing/chewing
Facial weakness
Shortness of breath
No pain, numbness

23. MG weakness
Farouk D, 2000

24. MG: Initial presentation and progression
Initial symptoms
Eye muscle weakness 75%
Head/neck weakness 15%
Limb weakness 10%
Within first year
~75% develop head/neck +/- limb weakness
~67% reach maximum MG severity
~20% experience severe exacerbation/MG crisis

25. Tensilon Test
Before
After

26. AChR antibody test Positive in 85% of MG patients
Antibody level does NOT correlate with disease severity between patients
In an individual patient, changes in antibody levels do correlate

27. “Antibody negative” MG
40-50% of patients with ocular MG
MuSK antibodies in 40% of AChR negative, generalized MG
“Low-affinity” antibodies in “double negatives” ??

28. Electrical tests
Repetitive nerve stimulation (RNS)
Single fiber EMG

29. 4. How is MG treated? Non-immune treatments Immune-directed treatments
Mestinon, etc.
“Band-aid”
Immune-directed treatments
Short-term
Plasmapheresis, IVIg
Long-term
Corticosteroids
Immunosuppressive drugs
Thymectomy?

30. Thymectomy? Does it Work? In which patients?
Thymoma
How old/young?
Ongoing international trial

31. Treatment must be individualized
Based on:
Age of onset
Status of thymus (CT scan)
Thymoma
Thymic hyperplasia
Antibody status
Severity/distribution of disease
Other medical problems

32. 5. Living with MG Prognosis Most patients do well with treatment
Little/no functional limitations
Your MG will likely not go away or be “cured”
You will probably need some drugs to control your MG (all have potential side effects)

33. Factors affecting MG Exercise Body Temperature
Illness, infections, stress
Menstrual cycle
Less when MG controlled

34. What can you do? Avoid overexertion Avoid catching infections
Avoid certain drugs
Eat a well-balanced diet and get plenty of rest, and some exercise

35. What about exercise? Guided by your own strength / endurance
Stop if you are fatigued, continue as you are if you are feeling good
The bottom line is that exercise is good within sensible guidelines
During “stable times,” you can follow as active a regime as anyone else
During a exacerbation ease off, and titrate your level of exercise the point at which you feel most comfortable.

36. Everyone’s different
Auburn's starting Quarterback from , he guided the Tigers to a 29-9 record
passer rating
Brandon Cox

37. Questions Is MG inherited? Is MG contagious? Why did I get MG?
Will my MG go away?
Will I be able to continue working?

38. Questions Can vaccination trigger or worsen MG?
Are there vaccines that MG patients should not have?
What is MG crisis?

39. Outlook is improving in MG!
Grob D (1999)

40. 6. The future Current The future Best-characterized autoimmune disease
Treatment is effective in most (but non-specific)
The future
What triggers MG?
What keeps it going?
What are the genetic factors?
Design a more specific treatment – CURE?

41. How is research in MG carried out?
Experimental MG
Patient-related research

42. Experimental MG Rabbits, rats, mice, etc.
Immunize with AChR from electric organs of electric eels or fish.
Weakness, Antibody responses

43. Experimental MG ε α α β δ AChR Baseline After neostigmine Muscle
Torpedo Californica
Baseline
Muscle
Acetylcholine
After neostigmine

44. MG – Clinical Trials
PHASE I TRIALS: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects, early evidence of effectiveness; may include healthy participants and/or patients.
PHASE II TRIALS: Controlled clinical studies conducted to evaluate the effectiveness and safety of the drug in patients.
PHASE III TRIALS: Expanded controlled trials provide and adequate basis for FDA labeling

45. What would be the ideal
treatment for MG?

46. The ideal immunotherapy
Treatment applied for a short time
Long-lived result
Target effects to autoreactive cells (Antigen-specific)
No side-effects
Immune
Tolerance
AutoReactive
Treatment
Immune
Tolerance

47. Obstacles
Treatment of autoimmune disease occurs months or even years after the onset of the disease process
Autoimmune response becomes more complex as disease progresses
Benefit achieved by interfering with the immune system’s defense mechanisms
Effective treatments to prevent rejection of transplants
Paucity of drugs that effectively treat autoimmune disease
Transplant : Acute challenge to an otherwise normal immune system
Autoimmunity: chronic, evolving disease

48. MG upsets the balance in the immune system
No MG MG

49. How do we restore the balance?
“The art of medicine consists in amusing the patient while nature cures the disease”       Voltaire ( )

50. How do we restore the balance?
Expand regulatory immune cells
Use agents (drugs) that promote their mobilization and growth
?Grow them in culture
Make them AChR-specific
? Stem cells

51. Summary
MG is caused by an abnormal immune response targeting the muscle (AChR, MuSK)
Most people with MG do well with the right treatment (treatment must be individualized).
You can live a normal life with MG.
We know a lot about the immune system defect in MG, but there are key questions that remain unanswered

52. Thank You
"Sleepy" (© Disney) of Snow White and the Seven Dwarfs was supposedly based on a friend of Walt Disney who had MG