brief presentation on mechanism, symptoms, investigations and treatment of myasthenia gravis.

1. MYASTHENIA GRAVIS
Dr. Ahmed Usman Khalid
Resident Ophthalmology
HMC

2. OUTLINE
• Background
• Anatomy
• Pathophysiology
• Epidemiology
• Clinical Presentation
• Treatment

3. BACKGROUND
• The word Myasthenia Gravis is derived from Latin and
Greek
Myasthenia – weakness
Gravis – serious
• literally means "grave muscle weakness"

4. • Myasthenia gravis (MG) - autoimmune disorder -
antibodies against AchRs at NMJ
• these antibodies attack and destroy AchRs & postsynaptic
molecules
• leads to impaired signal transduction, muscle weakness
and fatigability

5. ANATOMY
• Neuromuscular Junction (NMJ)
• Components:
Presynaptic membrane
Postsynaptic membrane
Synaptic cleft
• Presynaptic membrane contains Àch in vesicles
• ACh attaches to AChR on postsynaptic membrane

6. NEUROMUSCULAR JUNCTION

7. PATHOPHYSIOLOGY
• In MG, antibodies are directed toward the acetylcholine
receptor at the neuromuscular junction of skeletal
muscles

8. TYPES OF ANTIBODIES
• AChR antibodies – 90% in systemic cases and 50-70% in
ocular myasthenia.
• MuSK antibodies – positive patients are less likely to
have ocular features and thymoma.
• Striational antibodies – 80-90% of those with thymoma.
• Voltage-gated calcium channel antibodies – Lambert-
Eaton syndrome.

9. HOW DO THESE ANTIBODIES ACT?
1. Blocks the binding of ACh to the AChR.
2. Increases the degradation rate of AChR
3. A complement-mediated destruction
Results in:
nicotinic acetylcholine receptors
postsynaptic membrane folds
Widened synaptic cleft

11. EPIDEMIOLOGY
• Prevalence: 1-7 in 10,000
• Age: BIMODAL PEAK
• 20-30 yrs (young women), 50-60 yrs (older men)
• < 10% occur in children
• More common in pts with family history of one or the
other autoimmune diseases

13. Myasthenia
Gravis
Ocular Bulbar Generalized

14. SYSTEMIC MYASTHENIA
• Onset of symptoms in 3rd decade
• Fluctuating painless fatigue, commonly in conjunction
with ptosis and diplopia.
• Bulbar symptoms include dysphagia, dysarthria and
dysphonia.

15. SIGNS
• Most important feature is peripheral weakness.
Neck extensors > flexors
Upper limbs > lower limbs
Dropped head posture

16. Myopathic facies

17. • Respiratory weakness
Weakness of the intercostal muscles and the diaphragm
Collapse the upper airway
Neuromuscular emergency - mechanical ventilation

18. PROGRESSION OF DISEASE
• Mild to more severe over weeks to months
• Usually spreads from ocular facial bulbar
truncal limb muscles
• The disease remains ocular in 16% of patients
• Death rate reduced from 30% to <5% with
pharmacotherapy and surgery.

19. OCULAR MYASTHENIA
• Ocular involvement – 90%
• Presenting feature – 60%
• Ptosis
> bilateral , frequently asymmetrical
> typically worsen at the end of the day
> cogan twitch sign
• Diplopia
• Nystagmoid movements

22. ICE PACK TEST
• Ice pack is placed on ptotic eyelid for 2 minutes.
• MOA : cold inhibits the breakdown of acetylcholine by
acetylcholinesterase.
• 75% sensitive, highly specific.

23. Positive ice pack test in MG

24. EDROPHONIUM ( TENSILON TEST)
• Short-acting anticholinesterase
• Sensitivity – 85% in ocular and 95% in systemic MG
• Resuscitation facilities and appropriate expertise must
be readily available.

25. • Initial IV dose of 2 mg of edrophonium is given
• Observed for objective improvement in muscle weakness
• Definite improvement occurs-the test is considered
positive & terminated
• If no improvement in weakness - the remainder 8mg of
the drug is injected

27. MYASTHENIC CRISIS
• Exacerbation of weakness - endanger life
• Respiratory failure (diaphragmatic and inter costal
muscle weakness)
• Cause – intercurrent infection

28. TREATMENT
• There are four basic therapies:
Symptomatic treatment - acetylcholinesterase
inhibitors
Rapid short-term - plasmapheresis and intravenous
immunoglobulin
Chronic long term - immunomodulating treatment -
glucocorticoids & immunosuppressive drugs
Surgical treatment

29. ANTICHOLINESTERASE MEDICATIONS
• Pyridostigmine is the most widely used
• Onset - 15–30 min and lasts for 3–4 h
• Dose - 30–60 mg three to four times daily
• Frequency of the dose should be tailored to the patient’s
individual requirements throughout the day

30. NEOSTIGMINE
• Short-acting AChE inhibitor
• half-life - 45-60 minutes
• Poorly absorbed from the GIT
• Should be used only if pyridostigmine is unavailable

31. PLASMAPHARESIS
• Removes AChR Ab from the circulation
• Rapidly Improves strength
Used for
• short-term intervention
• Sudden worsening of myasthenic symptoms
• Chronic intermittent treatment for refractory cases

32. • Typically one exchange is done every other day for a total
of four to six times
• Improvement is noted in a couple of days, but it does not
last for more than 2 months.
• Complications – hypocalcemia, hypomagnesemia,
hypothermia, hypotension & transfusion reactions

33. INTRAVENOUS IMMUNOGLOBULINS
• Rapid improvement
• Severe myasthenic weakness
• Dose is 2 g/kg over 5 days (400 mg/kg per day)
• Improvement occurs in ~70% of patients
• Adverse reactions include headache, fluid overload, and
rarely aseptic meningitis or renal failure

36. IMMUNOSUPPRESSION
• Is required in nearly all pts with
- late-onset MG
- thymoma MG
- MuSK-MG
• Suppress autoantibody production & its detrimental
effects at NMJ

37. GLUCOCORTICOIDS
• First & most commonly used immunosuppressant
• Used when symptoms of MG are not adequately
controlled by cholinesterase inhibitors alone
• MOA - inhibits MHC expression & IL-1 production
decreased IL-2 & IFN γ production

38. PREDNISONE
• Most commonly used
• Decreases the severity of MG exacerbations
• Transient worsening might occur initially
• Clinical improvement - 2-4 weeks
• Marked improvement in 40%
• Remissions are noted in 30%

39. MYCOPHENOLATE MOFETIL
• Choice for long-term treatment
• MOA -prodrug of mycophenolic acid - Inhibits inosine
monophosphate dehydrogenase
• Lymphocyte proliferation and antibody production are
inhibited

40. • Does not kill or eliminate preexisting autoreactive
lymphocytes
• Clinical improvement may be delayed for 2-6 months
• Vomiting, diarrhoea, leucopenia and predisposition to
CMV infection, GI bleeds are the prominent adverse
effects.

41. AZATHIOPRINE
• It is a purine analog, reduces nucleic acid synthesis,
thereby interfering with T-and B-cell proliferation
• Is effective in 70%–90% of patients with MG
• When used in combination with prednisone - more
effective & better tolerated than prednisone alone
• Beneficial effect takes at least 3–6 months to begin

42. CYCLOSPORIN
• Used mainly in patients who do not tolerate or respond
to azathioprine
• Blocks synthesis of IL-2 cytokine
• Dose 4–5 mg/kg per day
• Cyclosporine can cause nephrotoxicity, neurotoxicity,
hepatotoxicity, hyperlipidemia, hyperuricemia,
hyperglycemia, hirsutism and gum hyperplasia

43. TACROLIMUS
• Is ~ 100 times more potent than cyclosporin
• It binds to FK 506 binding protein (FKBP) and causes
inhibition of helper T cells
• Beneficial effect appears more rapidly than that of
azathioprine
• less nephrotoxicity, hirsutism, hyperlipidemia than
cyclosporine
• Dose - 0.1 mg/kg per day

45. THYMECTOMY
• Carried out in all patients with generalized MG - aged
between puberty and 55 years
• Thymoma - Surgical removal is a must - possibility of
local tumor spread
• Up to 85% of patients experience improvement after
thymectomy
• Of these, ~ 35% achieve drug-free remission

47. 1. A 70 year old man complains of intermittent diplopia for the
past 3 years and denies any other systemic difficulties. Initially,
the examination seems normal. The patient is asked to sustain
left gaze (Fig A) but has difficulty as shown at 30 sec (Fig B)
and at 60 sec (Fig C). All of the following statements are true
except:

48. A. He is more likely to develop dysthyroidism than an otherwise
normal person his age.
B. The lack of AChR antibody in his blood makes MG an unlikely
diagnosis.
C. Cerebral MRI is unnecessary.
D. He is unlikely (<20% chance) to develop systemic muscular
weakness.

49. 2. A 22 year old man presents to the emergency department
with a 1 day history of diplopia. Examination reveals limitation
of abduction of right eye and limitation of elevation of left eye.
The pupil measure 7mm OD and 8mm OS with poor reaction to
light and accomodation. Bilateral ptosis is present. The least
useful test needed to confirm the diagnosis is:
A. Clostridium botulinum toxin test
B. Tensilon test
C. Lumbar puncture
D. GQ1b antibody test.

50. 3. A 67 year old woman developed variable double vision 1
month ago and appears to have fatigable ptosis. She has no
systemic symptoms. Which of the following statement is true:
A. A normal anti-acetylcholine receptor antibody level effectively
rules out MG.
B. Her risk of developing generalized myasthenia is about 20%.
C. The 30% occurrence of concomitant thyroid eye disease may
complicate the diagnosis of myasthenia.
D. An improvement of 2mm in ptosis following a 2 min ice
application to the eyelid confirms the diagnosis of myasthenia.

51. 4. A 56 year old female presents to ophthalmology OPD with
complaints of double vision and easy fatigability. She has ocular
motility deficit on examination. Upon inquiry, she mentions
that she was advised some investigations by another doctor
(shown below). What will be most appropriate step in the
management?

52. A. Start her on pyridostigmine and advise follow up after
3 months.
B. Perform tensilon test to confirm the diagnosis of MG.
C. Refer her to cardio-thoracic surgeon for further
management.
D. Counselling and keep under observation.

53. 5. A 60 years old male presents with history of double vision
and generalized weakness since 2 months. On examination, he
has ptosis and limited abduction in right eye. To confirm the
diagnosis of MG, tensilon test is performed in OT. During
procedure, patients pulse drops to 40/min and BP 90/60 mmHg.
What will you do next?
A. Give bolus dose of 0.9% normal saline.
B. Start IV dopamine to increase the heart rate.
C. Administer atropine 0.3mg IV stat.
D. None of the above.