1. Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin
MYASTHENIA GRAVIS
Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin

2. History of MG 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”
This has been interpreted as being the first written description of myasthenia gravis.
Thomas Willis (1621–1675)

3. History of MG
"The excessive fatigues he encountered wrecked his constitution.………………his eyelids were too heavy that he could not see unless they were lifted up by his attendants.“
While in Jamestown, Chief Opechancanough was able to rest and he then could raise himself up to a standing position.
Chief Opechancanough
Opchanacanough was a tribal chief of the Powhatan Confederacy of what is now Virginia in the United States, and its leader from sometime after 1618 until his death in 1646.

4. Epidemiology: Myasthenia Gravis
Most common disorder of NMJ transmission
Annual incidence of new cases per million
Prevalence: 14.2: (US) but on rise due to ↓ mortality, longer survival
The M:F ratio of MG in children and adults is 2:3.
Onset of MG at a young age is slightly more common in Asians than in other races
Age of onset has a bimodal distribution
Second and third decades (female predominance)
Sixth to eighth decade (male predominance)

6. Generalized Myasthenia (Grob et al. ‘81)

7. Ocular Myasthenia (Grob et al. ‘81)

8. Pathophysiology
To understand MG, familiarity with normal anatomy and functioning of NMJ is necessary.
The nerve terminal of the motor nerve enlarges at its end, which is called the bouton terminale (terminal bulb).
The presynaptic membrane (nerve membrane), postsynaptic membrane (muscle membrane), and synaptic cleft (space between the 2 membranes) constitute the NMJ.
Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.

9. NMJ Transmission Chemical synapses
Illustration of the major elements in chemical synaptic transmission.
An electrochemical wave called an action potential travels along the axon of a neuron.
When the wave reaches a synapse, it provokes release of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of another neuron, on the opposite side of the synapse.

10. Pathophysiology
MG is an autoimmune channelopathy: antibodies directed against the body's own proteins.
Autoantibodies [IgG] develop against ACh nicotinic postsynaptic receptors.
The antibodies are produced by plasma cells, derived from B-cells converted into plasma cells by T-helper cell stimulation.
Cholinergic nerve conduction to striated muscle is impaired and postsynaptic receptor are destroyed.
The cholinergic receptors of smooth and cardiac muscle are not affected by the disease.
Patients become symptomatic once the number of ACh receptors is reduced to about 30% of normal.
Serum IgG from MG patients increases degradation of AChR.

11. T-synaptic terminal Axon
M-Muscle cell.

12. NORMAL NMJ
ABNORMAL NMJ

13. Signs and Symptoms
The usual initial complaint is a specific muscle weakness rather than generalized weakness
Extra-ocular muscle weakness or ptosis is present initially in 50% of patients
The disease remains exclusively ocular in only 16% of patients
Rarely, patients have generalized weakness without ocular muscle weakness
Bulbar muscle weakness is also common, along with weakness of head extension and flexion
Limb weakness may be more severe proximally than distally
Isolated limb muscle weakness is the present in fewer than 10% of patients

14. Signs and Symptoms
Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb muscles
About 87% of patients have generalized disease within 13 months after onset
Less often, symptoms may remain limited to the extraocular and eyelid muscles for years
Weakness is least severe in the morning and worsens as the day progresses
Weakness is increased by exertion and alleviated by rest
Weakness progresses from mild to more severe over weeks or months, with exacerbations and remissions

15. PYSICAL EXAMINATION FOR MG
Muscle fatigability can be tested for many muscles.
A thorough investigation includes:
looking upward and sideward 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 sit-ups, 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

16. Additional Tests for MG Diagnosis
Ice pack test
Lightly placing ice that is in a surgical glove or that is wrapped in a towel over the eyelid will cool it within 2 minutes.
Positive test is clear resolution of the ptosis.
This test has a pooled sensitivity and specificity of 82% and 96%, respectively.
Patients with respiratory distress should have an evaluation of pulmonary function.
This evaluation includes pulse oximetry, a measure of pulmonary function ( PEFR, [FEV1]), and ABG sampling to determine PCO2 level.
Evidence of hypoxemia, poor respiratory effort, or CO2 retention is an indication for intubation and mechanical ventilation.

17. Tensilon Test Edrophonium is an AChE inhibitor.
Rapid onset (30s) and short duration of action (about 5 minutes).
Focus on a weak muscle group and evaluate for change.
Initial dose of 2mg given IV. If no change give additional 8mg IV.
Beware cholinergic effects (nausea, diarrhea, salivation, fasciculations, bradycardia).
Have atropine at bedside.

18. Additional Tests for MG Diagnosis
Anti–acetylcholine receptor antibody
(AChR) antibody (Ab) test is reliable for (MG).
Highly specific (100%).
Positive in 90% generalized MG.
50-70% ocular MG
False-positive anti-AChR Ab test results occur in:
Thymoma without MG
L-Eaton myasthenic syndrome
R A treated with penicillamine
Anti-MuSK– antibodies
About 1/2 Seronegative MG may have positive (Anti-MuSK antib)
Anti-MuSK (Muscle specific tyrosine kinase) positive individuals may have more pronounced
Bulbar weakness
Tongue and facial atrophy.
Neck, shoulder and respiratory involvement without ocular weakness.

19. Approximate sensitivity of the confirmatory tests for myasthenia gravis
Generalized myasthenia percent positive
Ocular myasthenia percent positive
AChR antibodies
80 to 90
40 to 55
MuSK antibodies (in AChR Ab negative patients)
40 to 50
<10
Repetitive nerve stimulation 75
<50
Single fiber electromyography
92 to 99
80 to 95
MG: myasthenia gravis; AChR: acetylcholine receptor; MuSK: muscle-specific kinase.

20. Other studies (Imaging)
Plain chest radiographs may identify a thymoma as an anterior mediastinal mass
Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all cases of MG
In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG
Thymoma

21. MG: DIFFFERENTIAL DIAGNOSIS
ALS
Basilar artery thrombosis
Brain stem gliomas
Cavernous sinus thrombosis
Dermatositis/Polymyositis
LEMS
Multiple sclerosis
Sarcoidosis & neuropathy
Thyroid disease
Tolosa-Hunt Syndrome
Mitochondrial myopathies ± external ophthalmoplegia
Neurasthenia
Oculopharyngeal muscular dystrophy
Botulism
Compressive lesions of cranial nerves
Congenital myasthenic syndromes

22. Repititve nerve stimulation
Anti-AChE inhibitors stopped 6-24 hrs prior to testing.
2-3 electric shocks/second delivered, action potentials recorded.
In normal individual, amplitude of evoked muscle action potential dose not change.
In MG, rapid reduction in the amplitude of the evoked response of more than 10-15%

23. Single Fiber EMG The most sensitive test for MG
Electrode measures action
potentials of two muscle fibers innervated by the
same motor axon.
Variability in time of the 2nd action potential relative to the 1st is called “jitter”.
MG causes increased “jitter”.

24. Anti-cholinesterase Inhibitor
AchE inhibitors
Initial treatment for mild MG
Pyridostigmine is used for maintenance therapy
Neostigmine is generally used only when pyridostigmine is unavailable
Corticosteroid therapy provides a short-term benefit
Azathioprine, usually after a dose of corticosteroids, is the mainstay of therapy for difficult cases
Cyclosporine A and occasionally methotrexate and cyclophosphamide are used for severe cases
Acetylcholine
Acetylcholinesterase

25. Cholinesterase Inhibitors
VIg
Moderate or severe MG worsening into crisis (no value in mild disease) [8]
Elderly patients
Patients with complex comorbid diseases (e.g., acute respiratory failure) 
Patients with severe weakness poorly controlled with other agents
Plasmapheresis
Generally reserved for myasthenic crisis and refractory cases
Also effective n preparation for surgery
Improvement is noted in a couple of days, but does not last for more than 2 months
Can be used long-term on a regular weekly or monthly basis can be used if other treatments cannot control the disease.

26. Immune modulation:
Most patients with generalized MG require additional immunomodulating therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids
The corticosteroid regimen should be tailored according to the patient’s overall improvement.
The lowest effective dose should be used on a long-term basis.
Because of the delayed onset of effects, steroids are not recommended for routine use in the emergency department (ED).
Other medications that are used to treat more difficult cases include
azathioprine,
mycophenolate mofetil,
cyclosporine,
cyclophosphamide
However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly

27. Plasmapheresis and IVIG
The response occurs over hours to days and is useful to treat or abort myasthenic crisis preoperatively.
Pathogenic antibodies removed at NMJ.
Usually a course of 5 exchanges over a 2 week
period is useful for relief
of symptoms.
IVIG
The recommended total monthly dose is 2 g/kg in five daily doses slowly enough to avert rate related side effects.
Half-life of IVIg is about 4weeks, and monthly doses are reasonable, with the goal of slowly tapering the frequency of treatments based on the clinical status.
Clinical responses occur over 2 to 4 weeks.

28. THYMECTOMY
Thymus has a central role in pathogenesis - thymectomy is an important part of Rx.
Radiographic/CT evidence of an anterior mediastinal mass warrants thymectomy at any age because 10% of patients with MG will have thymoma.
In the absence of mediastinal mass, it seems appropriate to counsel the patient to undergo thymectomy to increase the probability of sustained remission.
“Ernst Ferdinand Sauerbruch”, ( ) performed thymectomy for the relief of MG

30. THANK YOU FOR YOUR ATTENTION