Myasthenia gravis

1. Pratap Sagar
Tiwari, Lecturer, Internal
Medicine, NGMC, Nepal

2. PART ONE
• Neuromuscular junction
• Introduction of MG
• Types
• Epidemiology
• Clinical features
PART TWO
• Diagnostic approach
• Management

3. • MG is an autoimmune disorder characterized by
weakness and fatigability of skeletal muscles due
to dysfunction of the NMJ.
• These autoantibodies are thought to originate in
hyperplastic germinal centers in the thymus where
myoid cells expressing AChR are clustered.

4. • In ocular myasthenia, the weakness is limited to
the eyelids and extraocular muscles.
• In generalized disease, the weakness commonly
affects ocular muscles, but it also involves a
variable combination of bulbar, limb, and
respiratory muscles.

5. • Patients who have detectable antibodies to the
acetylcholine receptor (AChR) or to the musclespecific receptor tyrosine kinase (MuSK) are
considered to have seropositive MG, while those
lacking both AChR and MuSK antibodies are
considered to have seronegative MG.
• About half of pts with purely ocular MG are
seropositive, compared with approximately 90 %
of those with generalized disease.
• 10-15 % of patients with MG have an underlying
thymoma.

6. • The cardinal feature of myasthenia gravis is
fluctuating skeletal muscle weakness, often with
true muscle fatigue.
• The weakness may fluctuate throughout the
day, but it is most commonly worse later in the
day or evening, or after exercise.
• Early in the disease, the symptoms may be
absent upon awakening. Often as the disease
progresses, the symptom-free periods are lost;
symptoms are continuously present but fluctuate
from mild to severe.

7. Presenting symptoms
Ocular :50 %
(Ref:1)
Bulbar : 15 %
Limb weakness :<5 %
Isolated neck weakness :uncommon
Isolated respiratory :rare
Distal Limb :rare
1. Grob D, Arsura EL, Brunner NG, Namba T. The course of myasthenia gravis and therapies affecting outcome. Ann N Y Acad Sci 1987; 505:472.
2. Oosterhuis HJ. The natural course of myasthenia gravis: a long term follow up study. J Neurol Neurosurg Psychiatry 1989; 52:1121.

8. PART TWO
• Diagnostic approach
• Management

9. Muscle fatigability can be tested for many muscles. A thorough
investigation includes:
• looking
upward
and
sidewards
for
30
seconds: ptosis and diplopia
• looking at the feet while lying on the back for 60 seconds
• keeping the arms stretched forward for 60 seconds
• ten deep knee bends
• walking 30 steps on both the toes and the heels
• five situps, lying down and sitting up completely
• "Peek sign": after complete initial apposition of the lid
margins, they quickly (within 30 seconds) start to separate and
the sclera starts to show

10. • Bedside Test:
I. IcePack Test
II. Tensilon Test
• Serologic Testing:
I. Acetylcholine receptor antibodies
II. MuSK antibodies
• Electrophysiologic confirmation:
I. Repetitive nerve stimulation
II. Single-fiber electromyography

11. IcePack Test
• Since it is based on the physiologic principle of
improving neuromuscular transmission at lower
muscle T, the eyelid muscles are the most easily
cooled by the application of ice.
Tensilon Test
• Edrophonium chloride is an acetylcholinesterase
inhibitor with rapid onset (30 -45 secs) and short
DOA(5-10 min). This agent prolongs the presence of
acetylcholine in the neuromuscular junction and
results in an immediate increase in muscle strength
in many of the affected muscles.

12. • To perform the test, a test dose of 0.1 mL of 10 mg/mL
edrophonium solution is administered.
• If no response and no untoward effects are
noted, remainder of the drug (0.9 mL) is injected.
• Sinus bradycardia due to excessive cholinergic
stimulation of the heart is a serious complication;
consequently, an ampule of atropine should be available
at the bedside or in the clinic room while the test is
performed.

13. Binding AChR antibodies are are highly specific for MG.
These antibodies are present in approximately 80 to 90 %
of pt with GMG.
Essentially all patients (98 to 100 %) with MG and
thymoma are seropositive for these antibodies [1,2].
1.
2.
Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol 2004; 24:31.
Vernino S, Lennon VA. Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 2004;
10:7270.

14. • Antibodies to titin
• Antibodies to ryanodine
• Striated muscle Antibodies

15. • Repetitive nerve stimulation (RNS) studies and singlefiber electromyography (SFEMG) have a diagnostic
sensitivity in generalized myasthenia of about 75 percent
and 95 percent, respectively [1,2].
1.
2.
Oh SJ, Kim DE, Kuruoglu R, et al. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve 1992;
15:720.
Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol 2004; 24:31.

16. • Symptomatic treatments (anticholinesterase
agents)
• Chronic immunomodulating treatments
(glucocorticoids & other immunosuppressive
drugs)
• Rapid immunomodulating treatments
(plasmapheresis and intravenous immune
globulin)
• Surgical treatment (thymectomy)

17. • Oral
anticholinesterase
medication:
usually
pyridostigmine .
• Pyridostigmine has a rapid OOA :15-30 min with peak
action at about 2 hr , and its effects last for 3-4 hr and
sometimes longer.
• A common starting dose is 30 mg tid.
• When a patient has significant persistent weakness
despite the use of pyridostigmine in sufficient doses, or
the side effects preclude effective dosing, then
immunotherapy is generally warranted.

18. • Glucocorticoids and as well as other agents
azathioprine, mycophenolate mofetil and cyclosporine.
• TThe onset of benefit generally begins within two to three
weeks.
• However, a transient deterioration occurs in up to 50% of pts with MG when
high-dose glucocorticoids are started, usually occurring 5- 10 days after the
initiation .
• For this reason, glucocorticoids are most often started in high doses only in
hospitalized patients who are receiving concurrent plasmapheresis or
intravenous immune globulin (IVIG) for myasthenic crisis.

19. Time to onset
Time to maximal
effect
Symptomatic therapy
Pyridostigmine
10 to 15 minutes
2 hours
Chronic immunotherapy
Prednisone
2 to 3 weeks
5 to 6 months
Azathioprine
~12 months
1 to 2 years
Mycophenolate
mofetil
6 to 12 months
1 to 2 years
Cyclosporine
~6 months
~12 months
Rapid immunotherapies
Plasmapheresis
1 to 7 days
1 to 3 weeks
Intravenous immune
globulin
1 to 2 weeks
1 to 3 weeks
1 to 10 years
1 to 10 years
Surgery
Thymectomy

20. • The rapid therapies used in MG are also
immunomodulating but are distinct because of their quick
onset, transient benefit, and their use in select situations.
Both plasmapheresis and intravenous immune globulin
(IVIG) start to work quickly (over days), but the benefits
are only short term (weeks).
• These therapeutic modalities are used most often in the
following situations:
1. Myasthenic crisis
2. Preoperatively before thymectomy or other surgery
3. Periodically to maintain remission in patients with MG
that is not well controlled despite the use of chronic
immunomodulating drugs

21. • Plasmapheresis (plasma exchange) directly removes
AChR antibodies from the circulation.
• Course of treatment — A typical course of treatment
consists of 5 exchanges (3-5 L of plasma each) over 7-14
days.
• Complications
—
infection
and
thrombosis,bleeding, hypotension, cardiac arrhythmias .

22. •
IVIG is pooled immunoglobulin from thousands of
donors.
• MOA:uncertain. As with plasmapheresis, the effect of
IVIG is seen typically in less than a week, and the benefit
can last for 3-6 wks.
• Dose and side effects — The total dose of IVIG is 2
g/kg, usually over two to five days.
• The side effects include headache, chills, dizziness, and
fluid retention. Other uncommon complications include
aseptic meningitis, acute renal failure, thrombotic events,
and anaphylaxis.

23. • In
parallel
with
symptomatic
treatment
and
immunotherapeutic agents for MG, thymectomy is
considered because of its potential longer-term benefit.
• Thymectomy is advocated as soon as the patient's
degree of weakness is sufficiently controlled to permit
surgery.
• Thymectomy is not routinely suggested in patients over
60 years of age, unless a thymoma is present.

24. • Myasthenic crisis is a life-threatening condition, which is
defined as weakness from acquired myasthenia gravis
(MG) that is severe enough to necessitate intubation or to
delay extubation following surgery [1].
• Severe bulbar (oropharyngeal) muscle weakness often
accompanies the respiratory muscle weakness, or may
be the predominant feature in some patients. When this
results in upper airway obstruction or severe dysphagia
with aspiration, intubation and mechanical ventilation are
necessary.
1.
Bedlack RS, Sanders DB. On the concept of myasthenic crisis. J Clin Neuromuscul Dis 2002; 4:40.

25. Admit to intensive care unit
Measure FVC frequently, as often as every two hours if respiratory status is deteriorating
Electively intubate in the presence of any of the following conditions:
•
FVC less than 15 mL/kg body weight
•
Declines in serial measurements of FVC approaching 15 mL/kg
•
Clinical signs of respiratory distress
•
Difficulty handling oral secretions, swallowing, or speaking
Withdraw anticholinesterase medications to reduce airway secretions in patients who are
intubated
Begin rapid therapy with plasmapheresis or IVIG to treat myasthenic crises
Begin immunomodulating therapy with high dose corticosteroids (eg, prednisone 60 to
80 mg per day). Consider azathioprine, mycophenolate mofetil, or cyclosporine if steroids are
contraindicated or previously ineffective
Initiate weaning from mechanical ventilation when respiratory muscle strength is improving with
plasmapheresis or IVIG treatment, as quantified by a FVC >15 mL/kg

26. • With advances in therapy and intensive care
management, the prognosis in myasthenic crisis has
dramatically improved over the last four decades from a
mortality rate of 75 % to the current rate of <5 % [1,2].
1.
2.
Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol 2004;
24:75.
Alshekhlee A, Miles JD, Katirji B, et al. Incidence and mortality rates of myasthenia gravis and myasthenic crisis
in US hospitals. Neurology 2009; 72:1548.

28. References:
1. Uptodate 19.3
2. Harrison’s Internal medicine 18th ed.
3. Davidson’s Practice of Medicine