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

2. MYASTHENIA GRAVIS OVERVIEW
Historical Background
NMJ Physiology
Pathogenesis
Clinical Manifestations
Diagnosis
Treatment
Associated Conditions
Related Disorders

3. 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)

4. 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.

5. Epidemiology: Myasthenia Gravis
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)
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.

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

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

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

9. 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). It lies within a groove or indentation along the muscle fiber.
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.

10. 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.

11. Pathophysiology
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.
MG autoimmune channelopathy: antibodies directed against the body's own proteins
Autoantibodies [IgG] develop against ACh nicotinic postsynaptic receptors.
Slight genetic predisposition: HLA types B8 & DR3 predispose for MG. DR1 more specific for ocular myasthenia.
The antibodies are produced by plasma cells, derived from B-cells converted into plasma cells by T-helper cell stimulation.

12. NORMAL NMJ
ABNORMAL NMJ

13. ROLE OF THYMUS IN MG C. Weigert Frankfurt.
Thymomas were first noticed in MG patients in 1899
C. Weigert Frankfurt.
Drs Jacques Miller (London) and Bob Good (USA) in
1960s showed that the thymus was a key ‘immune
organ’. It generates ‘T cells’, the control freaks that
help to switch on other immune cells to make
antibodies and/or destroy germs.
1973 physiologists realized that the ACh, the ignition
keys, must somehow latch into specialized Ach
receptors (AChRs) – the ignition locks.
Basic scientists were using snake venoms to purify
AChR (from electric fish)
It was soon shown that most MG patients had
similar antibodies – so giving us a valuable diagnostic
test, which is now in routine use around the world
C. Weigert
Jacques Miller

14. Signs and Symptoms
Presenting symptoms of myasthenia gravis and the major considerations in the differential diagnosis
Presenting symptoms
Other disorders to consider
Ocular (50 percent)
Brainstem and cranial nerve lesions (including Horner's syndrome), thyroid ophthalmopathy, oculopharyngeal muscular dystrophy, chronic external ophthalmoplegia (mitochondrial disease)
Bulbar (15 percent)
Brainstem and multiple cranial nerve lesions, motor neuron disease, obstructive or malignant lesion of the nasal and oropharynx
Limb weakness (<5 percent)
Motor neuron disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and other motor neuropathies, multiple radiculopathies, Lambert-Eaton myasthenic syndrome, myopathies
Isolated neck (uncommon)
Motor neuron disease, inflammatory myopathy, paraspinous myopathy
Isolated respiratory (rare)
Motor neuron disease, acid maltase deficiency, polymyositis
Distal limb (rare)
Motor neuron disease, CIDP and other motor neuropathies, distal myopathies

15. Signs and Symptoms Ophthalmic symptoms Non-ophthalmic symptoms
75% initially complain of ptosis and diplopia.
90% of patients with MG develop ocular symptoms.
50% of patients will present solely with ocular symptoms, and about 50-60% of these patients will progress to develop generalized disease.
Ptosis may be unilateral or bilateral, and it may shift from eye to eye.
Non-ophthalmic symptoms
15% present with bulbar symptoms.
85% with bulbar weakness develop generalized weakness.
10% present with limb and trunk weakness.
85% of patients with generalized weakness will have limb muscles.
MG can lead to respiratory failure. Can be the first presentation of the disease.

16. Additional Tests for MG Diagnosis
Ice pack test
MG who has ptosis, placing ice over an eyelid will lead to cooling of the lid, which leads to improvement of the ptosis.
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. MYASTHENIA GRAVIS DIAGNOSTIC BLOOD TESTS
Anti–acetylcholine receptor antibody
(AChR) antibody (Ab) test is reliable for autoimmune (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,
1-3% of the population older than 70 years.
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.
Anti–striated muscle antibody
The anti–striated muscle (anti-SM) Ab test is also important in MG.
Anti-SM Ab is present in about 84% of patients with thymoma who are younger than 40 years
In individuals older than 40 years, anti-SM Ab can be present without thymoma.

18. 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.

19. Laboratory Studies MG Anti-acetylcholine receptor antibody
Positive in 74% of patients. (80% of patients with generalized myasthenia and in 50% of those with pure ocular myasthenia). False-positive anti-AChR occur in:
a) Thymoma without Myasthenia
b) Lambert-Eaton Syndrome
c) Small cell lung cancer
d) R A treated with Penicllamine
e) 1-3% population older than 70 years
Osserman Class
Mean Antibody Titer (x 10-9 M)
Percent Positive
R (Remission)
0.79 24
I (Ocular only)
2.17 55
IIA (Mild Generalized)
49.8 80
IIB (Moderate Generalized)
57.9
100
III (Acute Severe)
78.5
IV (Chronic)
205.3 89

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. THYMOMA ASSOCIATED WITH MG
Stage IVa thymoma in a 50-year-old man. Contrast-enhanced chest CT scan shows a primary mass (M) and a pleural drop metastasis (arrow)
CT showing Thymoma marked with blue arrow

22. 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

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

24. CONDITIONS THAT MIMIC MYASTHENIA GRAVIS
Motor neuron disease —(ALS) can involve the bulbar muscles, leading to facial weakness, dysarthria, or dysphagia. However, ptosis or diplopia as typically seen with MG are NOT features of ALS
Lambert-Eaton myasthenic syndrome — shares with MG the involvement of the neuromuscular junction, and it has a similar pathophysiology (an autoimmune disease often associated with malignancy).
Penicillamine-induced myasthenia — Approximately 1 percent of patients treated with penicillamine, usually for rheumatoid arthritis or Wilson's disease, develop an autoimmune myasthenia gravis that shares many of the characteristics of primary MG
CONDITIONS THAT MIMIC OCULAR MYASTHENIA —
 They include the following conditions:
Thyroid ophthalmopathy
Chronic progressive external ophthalmoplegia
Myotonic dystrophy and oculopharyngeal dystrophy
Brainstem and motor cranial nerve pathology
CONDITIONS THAT MIMIC GENERALIZED MYASTHENIA 
Generalized fatigue — Although fatigable weakness may be a major aspect of MG, it is important to differentiate this from complaints of generalized fatigue or tiredness.
Statins and myasthenia — Statin treatment may be associated with a myasthenic syndrome or exacerbation of myasthenia symptoms

25. 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.

26. Ice pack test 
The ice pack test can be used in patients with ptosis, particularly those in whom the edrophonium test is considered too risky.
It is not helpful for those with extraocular muscle weakness.
Since it is based on the physiologic principle of improving neuromuscular transmission at lower muscle temperatures, the eyelid muscles are the most easily cooled by the application of ice.
In the ice pack test, a bag (or surgical glove) is filled with ice and placed on the closed lid for two minutes. The ice is then removed and the extent of ptosis is immediately assessed.
The sensitivity appears to be about 80 percent in those with prominent ptosis.
The predictive value of the test has not yet been established.

27. 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%

28. 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”.

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

30. Associated Conditions
Disorders of the thymus
Thymoma
Hyperplasia of thymus
Autoimmune disorders
Thyroiditis
Autoimmune thyroid disease (3-8%) RA
SLE
Lymphoid Hyperplasia
Rebound Hyperplasia secondary to
Chemotherapy
Radiotherapy
Corticosteroid Therapy
Thermal Burns
Systemic Stress
MG can be exacerbated by hyper/hypothyroidism, occult infection or drugs.

31. MG TREATMENT OPTIONS Ache inhibitors
Pyridostigmine (Mestinon) is the most commonly used AChE inhibitor.
Peak serum concentrations reach in 90 to 120 minutes and has a similar half-life.
60 to 120 mg every 3 to 4 hours are most effective.
Patients may modify their dose to match their level of activity and to reduce the common adverse side effects of cramping and diarrhea.
It is rare for pyridostigmine alone to improve transmission to a satisfactory level, and therefore most patients require more definitive therapy.

32. MG PHAMACOLOGICAL AND PYSIOLOGICAL ADVANCES
Sir Henry Dale English physiologist-pharmacologist
Showed that "the actions of acetylcholine are both muscarinic and nicotinic, and at different synapses exert different effects which can be differently antagonized”.
Another application came in the recognition of physostigmine, drug that block the enzymatic destruction of acetylcholine, and so allow this substance to accumulate in cases of deficiency, as in myasthenia gravis.
Dale shared Nobel Prize in 1936 for developing the theory of neurohumoral transmission.
Sir Henry Dale( )

33. Curare– Calabar Bean--
February, January, 1920
July 12, 1813-February 10, 1878
Sir TR Fraser (1860) and his team in Edinburgh found that the Calabar bean poison protects against curare, and they then purified physostigmine from it.
Claude Bernard (1850) French Physiologist showed that the arrow poison Curare works by blocking NMJ. (It is now used to relax muscles during surgery).

34. Anti-cholinesterase Inhibitor
Anti-cholinesterase Inhibitor (AChEI) inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.
Acetylcholinesterase inhibitors:
Occur naturally as venoms and poisons.
Are used as weapons in the form of nerve agents.
Are used medically:
In myasthenia gravis, to prevent enzymatic breakdown of ACh to increase neuromuscular transmission.
In the treatment of Glaucoma.
To treat Alzheimer's disease.
To treat Lewy Body Dementia.
As an antidote to anticholinergic poisoning.
Acetylcholine
Acetylcholinesterase

35. Cholinesterase Inhibitors
MG is one of the most treatable neurologic disorders.
These agents increase the amount of available ACh at the NMJ by inhibiting the degradation of ACh.
Most patients are able to titrate the dosage of their medication to control the symptoms of the disease, but severe exacerbations can occur in patients with previously well-controlled disease
Pyridostigmine is the most used AChE inhibitor.
Peak serum concentrations reach in 90 to 120 minutes and has a similar half-life.
60 to 120 mg every 3 to 4 hours are most effective.
Patients may modify their dose to their level of activity
It is rare for pyridostigmine alone to improve transmission to a satisfactory level, and therefore most patients require more definitive therapy.

36. 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

37. MYASTHENIA GRAVIS TREATMENT
Mary Broadfoot Walker (1888—1974) was a British physician who first demonstrated the effectiveness of physostigmine in the treatment of myasthenia gravis.
She had noted that the symptoms and signs of myasthenia were similar to those found in curare poisoning, and physostigmine was used as an antidote to curare poisoning at that time.
The first case of MG successfully treated with physostigmine was published in the Lancet in June 1934.
Mary Broadfoot Walker

38. MYASTHENIA GRAVIS TREATMENT
She was the first to recognize (1935) the association between the condition familial periodic paralysis and hypokalaemia.
Described the glucose challenge test used in diagnosing hypokalaemic periodic paralysis and the use of intravenous potassium in its treatment.
In1935 her research on myasthenia was incorporated into her MD thesis which was submitted via the University of Edinburgh and for which she received a Gold Medal.
Although she never became a Fellow of the Royal College of Physicians she was awarded the Jean Hunter Prize in 1962
Mary Broadfoot Walker

39. 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.

40. 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”,
German surgeon ( ) performed thymectomy for the relief of myasthenia gravis.

41. EVIDENCE BASED EFFECTIVENESS OF THYMECTOMY IN MG
Fifty-six board-certified neurologists with interest and expertise in myasthenia completed a survey of indications for thymectomy in myasthenia gravis.
Thymectomy was advocated for virtually all patients with thymoma.
Variable subset of patients with generalized myasthenia without thymoma.
Occasionally for selected patients with disabling ocular myasthenia.

42. A M I T B H C N A R I S O N H E N M C K I G R O G E S M I T H

43. THANK YOU FOR YOUR ATTENTION