1. Myasthenia Gravis 重症肌无力(MG)
Department of Neurology
Ruijin Hospital
Myasthenia gravis (MG) is an acquired disease of the neuromuscular junction characterized by muscular weakness and fatigability. involved in muscles of the face and extremities. 1

2. Outline Introduction Etiology and Pathogenesis
Pathology&Pathophysiology
menifestation
Diagnosis&Differential Diagnosis
Management 2

3. Introduction Acquired autoimmune disease
Inability of signal transmission within the neuro-muscular junction (NMJ)
Clinically characterized by:
Fatigue of skeletal muscles
Deterioration on movement
Alleviation on cholinesterase inhibitors
Incidence: (0.5-5)/100,000
Prevalence: 10/100,000
Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by weakness and fatigue of the skeletal muscles of the face and extremities. the cause of myasthenia gravis is a breakdown in the normal communication between nerve and muscles.The name of myasthenia gravis , which is latin and greek in origin,the literally means grave muscle weakness. with current therapies, however, most cases of mgare not as grave as the name implies. In fact, for the majority of individuals with MG, life expectancy is not lessened by the disorder. 3

4. Etiology and Pathogenesis
Normally when impulses travel down the nerve, the nerve dendings resealse a neurotransmitter substance called acetylcholine, Ach tracels through the neuromuscular junction and binds to Ach receptors which are activited and generate a muscle constration.
The chronic inflammation of MG causes several changes in the structure of the Neuromuscular Junction which also inhibit transmission and contribute to weakness. These include flattening out of the junctional folds, spreading out of AChR and Acetylcholinesterase, a 66% decrease in number of AChR, and an increased junctional gap.

5. Pathology Muscular morphology was normal in most cases
loss of synaptic folds and widened clefts
thymoma with MG
15% of MG patients have thymoma of the lymphoepithelial type
70% have lymphoid hyperplasia of the thymus：numerous germinal centers
In about 50% of cases, muscles contain lymphorrhages, which are focal clusters of lymphocytes near small necrotic foci without perivascular predilection
loss of synaptic folds and widened clefts
residual synaptic showing Y-shaped antibodylike structures, IgG, complement components 2 and 9, and complement membrane attack complex
Hypertrophy(65%)
Thymoma(10-20%)
muscles contain lymphorrhages 5

6. Pathophysiology
In MG, antibodies are directed toward the acetylcholine receptor at the neuromuscular junction of skeletal muscles
Results in:
Decreased number of nicotinic acetylcholine receptors at the motor end-plate
Reduced postsynaptic membrane folds
Widened synaptic cleft
Induciton of a myasthenic-like syndrome in mice by injecting a large quantitiy of immunoglobulin G from MG patients

7. Clinical Presentation-(1)
MG occurs at any age
Onset summit: 20-40y(F>M), 40-60y(M>F)
10% onset before 10y
Thymoma was frequently seen in late onset patients
Mostly insidious and progressive
Muscle weakness

8. Clinical Presentation-(3)
Weakness could be seen in all skeletal muscles.
Ptosis,diplopia,oropharyngeal muscle weakness –difficulty in swallowing and talking, or limb weakness
fluctuates and progressively worsens over course of day
worsens with prolonged use of affected muscles (i.e. fatiguable)

9. Ocular Ptosis(dropping eyelid) – asymmetric, fatigues with upgaze
Diplopia(double vision) – most common involved MR(medial rectus )
In most cases, the first noticeable symptom is weakness of the eye muscles. can mimic any pattern of ophthalmoplegia including pupil sparing IIIrd nerve palsy, internuclear ophthalmoplegia (INO) or sixth nerve palsy
generally progresses over time so that within 2 years of onset of ocular MG, 90% have bulbar and proximal symmetric limb weakness 9

10. Bulbar Limbs Respiratory muscles Axial muscles Exertional dyspnea
Dysarthria
Dysphagia
Dysphonia
Masticatory weakness
– jaw closure > jaw open
Exertional dyspnea
Tachypnea
Respiratory failure
(Myasthenic crisis)
Axial muscles
Limbs
difficulty in swallowing and slurred speech may be the first signs in some patients. Bulbar involvement common eventually dysphagia, dysarthria, dysphonia (hypernasal or hoarse)
reduced facial expression, jaw fatigue
Weakness may affect the neck, arms, legs usually preffer affected proximal than distal
Neck flexion
Neck extension
Commonly proximal, symmetric
Arms more affected than legs 10

11. Clinical Presentation -(5)
MG Crisis
defined as the need for assisted ventilation
arises in about 10% of myasthenic patients
more likely to occur in patients with dysarthria, dysphagia, and documented respiratory muscle weakness
may also occur in other patients after respiratory infection or major surgery
A Myasthenia Gravis crisis involves several breathing difficulties (shortness of breath) due to muscle weakness. A crisis is defined as being unable to breathe to the point that one needs a ventilator, which is a breathing machine. crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress
In a crisis, the most dangerous signs are breathing and throat muscle weakness. The shortness of breath may become severe enough to require hospitalization for breathing support (ventilator), as well as treatment for the underlying infection. If the problem is not identified and treated correctly, it could lead to death.
It is important for MG patients to notify their neurologists with symptoms of shortness of breath.
It is estimated that the rate of extubation failure in myasthenic crisis is around 27% and the risks of failure are higher in older people, in patients with pneumonia or atelectasis or in those who required prolonged care in intensive care unit. 11

12. Clinical Presentation -(5)
Categorization of MG Crisis
Myasthenic crisis
acetylcholine insufficiency
Cholinergic crisis
acetylcholine overmuch
Brittle crisis
non susceptivity to acetylcholine 12

13. crisis Myasthenic Cholinergic Brittle incidence More often less
perspiring
little
much
uncertain
dribbling no
abdominal pain
obvious
fasciculation
pupil
normal
smaller
Reaction toChEI
ameliorate
aggravate
no reaction
atropin
No reaction
Precipitating factor
Infection delivery
ChEI over
not clear
Myasthenic crisis An acute ↑ in requirement for anticholinesterase therapy or refractoriness to same, diagnosed by a Tensilon test, with transient ↓ of symptoms
Cholinergic crisis An acute ↓ in the need for anticholinesterase medication, resulting in 'overmedication' with the customary doses; the Tensilon test exacerbates this form of myasthenic crisis; cholinergic crises may be either
• Muscarinic crisis Abdominal pain, diarrhea, nausea, vomiting, lacrimation, blurred vision, bronchial hypersecretion due to parasympathetic hyperresponse
• Nicotinic crisis Muscle weakness, fasciculations, cramping and dysphagia, due to overdepolarization at the neuromuscular junction. See Tensilon test 13

14. Osserman Classification of MG-(1)
Based on the severity of the disease
1、Adult MG
Ⅰ.Ocular myasthenia(15-20%)
Ⅱ(a).Generalized MG of mild intensity(30%)
Ⅱ(b) .Generalized MG of moderate intensity(25%)
Ⅲ.Severe generalized disease(15%) with respiratory failure: Intubation needed to maintain airway
Ⅳ. generalized disease due to type Ⅰ,Ⅱ(a),Ⅱ(b) getting worse
Ⅴ.Myasthenic Gravis with muscle atrophy in early stage.
The Osserman classification consists of four grades: Grade I, focal disease (restricted to the ocular muscle);
grade II, generalized disease that is either mild (IIa) or moderate (IIb); grade III, acute severe generalized
disease with respiratory failure; and grade IV, severe generalized disease with respiratory failure
(progression within 2 years). 14

15. Osserman Classification of MG-(2)
2、Childhood MG (account for 20% in Chinese MG patients)
(1) Neonatal MG: most cases recovered after 1w to 3ms’ treatment
(2) Congenital MG: mostly resistant to AchR inhibitors; family history
3、Teenager MG: onset from 14y to 18y.
Most cases only presented with ocular symptoms
The Osserman classification consists of four grades: Grade I, focal disease (restricted to the ocular muscle);
grade II, generalized disease that is either mild (IIa) or moderate (IIb); grade III, acute severe generalized
disease with respiratory failure; and grade IV, severe generalized disease with respiratory failure
(progression within 2 years). 15

16. Diagnostic tests Fatigue test（Jolly test） Neostigmine Test
Blink eyes for 30 consecutive times
Holding arms horizontally
Crouching for consecutive times
Neostigmine Test
1.5mg neostigmine methylsulfate for adults
Alleviation within 10-20m post injection is (+)
0.5mg atropine was simultaneously injected for prevention of side effects

17. Neostigmine test A: Severe ptosis of the lids.
B: Same patient 1 minute after intravenous injection of edrophonium (10 mg). (From Rowland LP, Hoefer PFR, Aranow H Jr. Myasthenic syndromes. Res Publ Assoc Res Nerv Ment Dis 1961;38; with permission.) 17

18. Diagnostic tests Repetitive nerve stimulation
Single fiber electromyography
progressive decrement in the amplitude of muscle action potentials
a. Slow: 2-3/second fifth wave decrease >10%
b. Fast: >10/second fifth wave decrease >30%
The mean interpotential difference between two fibres is called “jitter” and is normally less than 55 µsec. In MG, this interval or jitter is increased and is usually >100 µsec. 18

19. Diagnostic tests 1.Antibodies to AChR
generalized MG :>80%
iocular MG:50%
MG and thymoma:98-100%
The titer does not match the severity of symptoms
2. Anti-muscle specific receptor tyrosine kinase (MuSK) antibodies
Used if MG suspected, patient seronegative
Present in 40–50% of seronegative patients with generalized MG; absent in ocular MG 19

20. Diagnostic tests-(5)
Radiographs of the chest provide evidence of thymoma in about 15% of patients, especially in those older than 40 years.
CT of the mediastinum demonstrates all but microscopic thymomas.
thymoma
hyperplasia of the thymus 20

21. Diagnosis Procedure When to suspect? Fluctuating Weakness
Better in the morning, worse in the afternoon
Positive fatigue test
How to confirm?
Neostigmine test
Repetitive nerve stimulation
SFEMG
Anti-AchR antibody titters
a medical test used to distinguish the muscle weakness found in myasthenia gravis and Eaton-Lambert syndrome. Jolly's test is a type of electromyography which uses repeated stimulation of motor nerves to demonstrate the fatiguability found with repeated muscle contraction which is seen in myasthenia but not Eaton-Lambert syndrome.[1] 21

22. Differential diagnosis
Lambert-Eaton syndrome
Chronic inflammatory muscular disorders
Ocular muscle dystrophy
Progressive bulbar palsy
Clostridium botulinum intoxication
Muscular dystrophies are genetic diseases and having MG does not put you at risk for developing such a disease. In fact, the eye muscles, which we studied in patients with advanced DMD, are always spared, in contrast to the eye muscles in MG that tend to be affected early in the disease.
An accurate diagnosis of either ALS or MG is a good history, physical exam, review of the patient’s imaging and EMG findings. When an experienced neuromuscular neurologist puts this information together, it is uncommon to confuse the two. MG does not cause increased reflexes, dramatic slowing of movements, or enlarged motor unit potentials on EMG. MG has a number of features (double vision, droopy eyelids) that are not seen in ALS. They also have many share features.
Myasthenia Gravis causes muscle weakness that becomes significantly worse with activity. Double vision, swallowing and speaking abnormalities, difficulty walking and using the arms are common symptoms. Lambert-Eaton Myasthenic Syndrome (LEMS) may produce similar symptoms, as well as muscle aches and dry mouth, but double vision is less common. Patients may also have impotence, constipation, impaired sweating, blurred vision and difficulties with urination.
Myasthenia Gravis is an autoimmune disease in which antibodies damage the acetylcholine receptors and compromise the muscle side of the nerve-muscle communication point. LEMS is an autoimmune disease that affects the nerve and not the muscle. LEMS may be triggered by a lung cancer. An EMG test performed by an experienced neurologist differentiates Myasthenia Gravis from LEMS. Blood tests for certain antibodies may also help with their differentiation. Many of the treatments for the disorders are similar, although patients with LEMS may not respond as well. A thymectomy is not used to treat LEMS. 22

23. Management -(1) Management with medicine Contraindicated drugs
Anticholinesterase drug(Mestinon max60mg,q4h)
Cortisones（could worsen the disease in short term, side effects could be fatal）
Immune suppress agents（ azathioprine, cyclophosphamide, cyclosporine A, etc）
Contraindicated drugs 23

24. Management -(2) Thymus-targeted therapy
indication
thymoma, hypertrophy of thymus, drug-resistant patients
contra-indication
<18y, non-severe
effective for 70% patients
sometimes worsens 24

25. Management -(3) Plasmapheresis Intravenous Immunoglobulin (IVIg)
remove Ach-R antibodies of serum
effective but not consistent
used in case of MG crisis
Intravenous Immunoglobulin (IVIg)
effective
side effects were rare
widely used in clinical practice
0.4g/(kg d), iv. 3-5 days/course
interfere the function of Ach-R antibodies 25

26. Management -(4) Artificially facilitated breath is urgently needed
Anti-infection therapy is frequently needed
Cortisones
Myasthenia Crisis: increase doses of neostigmine
Choligernic Crisis: stop using neostigmine
Brittle Crisis: stop using neostigmine
A Myasthenia Gravis crisis involves several breathing difficulties (shortness of breath) due to muscle weakness. A crisis is defined as being unable to breathe to the point that one needs a ventilator, which is a breathing machine. crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress
In a crisis, the most dangerous signs are breathing and throat muscle weakness. The shortness of breath may become severe enough to require hospitalization for breathing support (ventilator), as well as treatment for the underlying infection. If the problem is not identified and treated correctly, it could lead to death.
It is important for MG patients to notify their neurologists with symptoms of shortness of breath.
It is estimated that the rate of extubation failure in myasthenic crisis is around 27% and the risks of failure are higher in older people, in patients with pneumonia or atelectasis or in those who required prolonged care in intensive care unit. 26

27. Summary Acquired autoimmune Disease
Antibodies attack the Acetylcholine receptor.
the ocular, bulbar and proximal skeletal are more likely affected
Fatigability is a key symptom!
Disease has a fluctuating pattern of ‘crises’ and remittances.
Treatment is usually with Acetylcholinesterase inhibitors and immunosupression
Easily treated and would have a good life expectancy. 27

28. Thanks！ 28