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Myasthenia gravis
1. MRS. M. PRADEEPA MPT (NEURO)
VICE PRINCIPAL
PPG COLLEGE OF PHYSIOTHERAPY
COIMBATORE, TAMILNADU, INDIA
2. INTRODUCTION
Myasthenia gravis is a disorder of neuromuscular
transmission
This condition is a consequence of an autoimmune
destruction /auto antibodies formation against
NICOTINIC POSTSYNAPTIC RECEPTORS FOR
ACETYLCHOLINE at the neuromuscular junction of
skeletal muscles.
3. History
First recognised by Oxford physician Thomas Willis in 1672.
The first modern description - Samuel Wilks, a London
physician in 1877 - described bulbar and peripheral muscular
weakness without any CNS pathology.
The first full descriptions of Myasthenia gravis were by the
German physicians Wilhelm Erb in 1879 and Samuel Goldflam
in 1893
The term "Myasthenia gravis pseudo-paralytica" was proposed
in 1895 by Jolly, a German physician
In 1901, Carl Weigert, a German pathologist (1845–1904), first
described a myasthenic patient with a thymic mass
4. Medical history
Mary Walker treated a person with MG
with physostigmine in 1934.
In 1937, Blalock established the removal of thymus as a
treatment for MG.
Simpson and Nastuck suggested the autoimmune etiology
of MG in 1959–1960 depending on several observations.
In the 1970s, prednisolone, azathioprine, and, later,
plasma exchange were established as treatments for MG.
5. Definition
Myasthenia gravis (MG) is a relatively rare
acquired, autoimmune disorder caused by an antibody-
mediated blockade of neuromuscular transmission
resulting in skeletal muscle weakness.
The word is from the Greek "mys" "muscle" and
"astheneia" "weakness", and the Latin "gravis" "serious".
It is a type-II hypersensitivity immune response.
8. Epidemiology
The worldwide prevalence of MG is 100–200 per million
population, affecting more than 700,000 people all over the
world
Bimodal distribution with a female predominance in the 2nd to
3rd decade of life and male predominance in the 6th to
8th decades
Female-to-male ratio for incidence is 3:2 in people below the
age of 30 and 1:1.5 in people more than 50 years of age.
Life-threatening MG crises occur approximately in 15–20% of
patients, typically within the first 2 years of diagnosis
9. ETIOLOGY
MG is idiopathic in most patients
Thymic abnormalities are
1. 75% have thymic disease,
2. 85% have thymic hyperplasia,
3. 10–15% have thymoma.
Extrathymic tumors may include small cell lung cancer and Hodgkin
disease.
Hyperthyroidism is present in 3–8% of patients with MG and has a
particular association with ocular MG.
Genetic predisposition linked to human leukocyte antigen complex
Risk factors - positive personal or family history of autoimmune
disease like rheumatoid arthritis, HLA-B8, DR3, and women being
less than 40 and men more than 60 years of age.
10. Classification
Congenital myasthenia gravis: a genetic defect
Ocular myasthenia gravis
Generalized myasthenia gravis
Transient neonatal myasthenia gravis: Infants born to
mothers with myasthenia gravis may develop symptoms of the
disease about 48 hours after birth. Symptoms can include
impaired sucking and swallowing, a weak cry, and respiratory
insufficiency. The symptoms typically disappear within days or
weeks.
Juvenile myasthenia gravis: symptoms begin before the
onset of puberty
11. Pathology
Changes are found in the THYMUS gland and in muscle.
The main function of the thymus is to affect the production of
T-cell lymphocytes, which participate in immune responses.
The gland is most active during the induction of normal
immune responses in the neonatal period and attains its largest
size at puberty after which it involutes.
In myasthenia gravis: 20% - involuted gland, 70% - show
hyperplasia with lymphoid follicles demonstrating germinal
centres, 10% thymoma, and encapsulate tumour of lymphoid
and epithelial cells which may be locally invasive but rarely
metastases.
The thymus gland may give wrong instructions to immune cells
12. The disorder occurs when the immune system malfunctions
and generates antibodies
Antibodies bind to the receptor sites in post synaptic area
resulting in their destruction
These antibodies are referred to as acetylcholine receptor
antibodies (AChR antibodies 80 – 90%)
AChR antibodies in MG attack a normal human protein, the
nicotinic acetylcholine receptor, or a related protein
called MuSK 5- 7% a muscle-specific kinase.
Other less frequent antibodies are found
against LRP4, Agrin and titin proteins
13. Pathophysiology
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Ach was released normally
AchR antibodies binding in the postsynaptic membrane
Results in destruction and reduction in the number of available Ach receptors
on the muscle end plate membrane (binding site for Ach)
An inconsistent generation of muscular action potentials manifesting as
muscle weakness
14. Pathophysiology
In patients without antibodies against AChRs, a muscle-
specific tyrosine kinase (MuSK), an agrin-dependent
protein on muscle membrane, has been found to be the
antigenic target. These autoantibodies are T-cell dependent
and there is interesting differential involvement of muscle
groups, especially the extraocular muscles.
15.
16. Clinical features
Fatigable weakness, involving specific susceptible groups of muscles, is
the clinical hallmark of MG. This weakness usually fluctuates from hour
to hour, day to day, worsens with activity, and improves on rest
The demonstration of fatiguing is important in reaching diagnosis and in
monitoring the response to treatment:
1. Look upwards - Ptosis becomes apparent and the eye drifts to neutral
position
2. Look left – ptosis becomes apparent and a dysconjugate drift develops
Fatiguing of other bulbar muscles may be demonstrated by:
1. blowing out cheeks against pressure.
2. counting as far as possible in one breath, etc.
17. Clinical features
Group of muscle Clinical features
Ocular muscle Fluctuating ptosis and/or diplopia
Bulbar muscle Dysarthria, painless dysphagia, dysphonia, and masticatory weakness,
The tongue occasionally shows the characteristic triple grooved
appearance with two lateral and one central furrow.
Facial muscle Facial weakness, inability to close eye firmly, drooling of saliva,
expressionless appearance.
On smiling, buccinator weakness produces a characteristic smile
Myasthenic snarl.
Axial muscular Weakness of neck muscles - lolling of the head
Limb muscle Weakness involving the arms more than legs, hyperactive limb reflexes ,
fatigue on repeated testing. Muscle wasting - 15% of cases
Respiratory muscle Labor breathing, orthopnea, dyspnea, and respiratory failure –
Myasthenic crisis
19. Clinical classification - MGFA
Class Clinical description
Class 1
Any eye muscle weakness, possible ptosis, all other muscles’ strength is
normal
Class 2
2a
2b
Mild weakness of other muscles; may have eye muscle weakness of any
severity
Predominantly limb or axial muscles weakness or both
Predominantly oropharyngeal or respiratory muscle weakness or both
Class 3
3a
3b
Moderate weakness of other muscles; may have eye muscle weakness of
any severity
Predominantly limb or axial muscle weakness or both
Predominantly oropharyngeal or respiratory muscle weakness or both
Class 4
4a
4b
Severe weakness of other muscles; may have eye muscle weakness of any
severity
Predominantly limb or axial muscle weakness or both
Predominantly oropharyngeal or respiratory muscle weakness or both; use
of feeding tube without intubation
Class 5 Intubation needed to maintain airway
20. Differential diagnosis
Chronic fatigue syndrome
Progressive ophthalmoplegia, e.g. mitochondrial myopathy,
oculopharyngeal dystrophy.
Multiple sclerosis – diplopia, dysarthria and fatigue with a
relapsing and remitting course.
Lambert-Eaton myasthenic syndrome: It is a rare presynaptic
disorder of neuromuscular transmission in which quantal
release of acetylcholine (ACh) is impaired, causing a unique
set of clinical characteristics, which include proximal muscle
weakness, depressed tendon reflexes, post tetanic potentiation,
and autonomic changes.
21. Investigation
Pharmcological: Anticholinesterase drugs are used to confirm
diagnosis.
Tensilon test: (edrophonium) – short action, 2–4 minutes,
given i.v. 2–10 mg slowly, with atropine pretreatment to
counter muscarinic side effects (nausea and bradycardia –
resuscitation facilities need to be available).
This is positive when clear improvement in weakness occurs
on objective testing.
A control injection of saline and blinded observer can be
useful.
The Tensilon test may be negative in ocular myasthenia and
give a false positive in the Lambert-Eaton
22. Serological investigation
Acetylcholine receptor antibodies (anti-AchR) are detected in
90% of patients and are virtually specific to this disease.
In ocular myasthenia, only 60% show antibodies.
Anti- Muscle specific Kinase (anti-MUSK) antibodies are
found in a proportion of anti-AchR negative patients.
Other antibodies e.g. microsomal, colloid, rheumatoid factor,
gastric parietal cell antibody – are occasionally found,
reflecting the overlap with other autoimmune disorders.
Anti striated muscle antibodies are found in 30% of all patients
and in 90% of those with thymoma.
23. Electrophysiological investigation
Reduction of the amplitude of the compound muscle
action potential evoked by repetitive supramaximal nerve
stimulation – ‘the decrementing response’.
Various rates of stimulation; even as low as 3/second may
produce a decrementing response.
Single fibre electromyography – measure of ‘Jitter’ – the
time interval variability of action potentials from two
single muscle fibres of the same motor unit – is a more
sensitive index of neuromuscular function and is increased
(95% of mild cases are abnormal).
24. Imaging test
Chest X ray will show a large mediastinal mass but will
not exclude a small thymoma.
CT of chest should be performed in all newly diagnosed
cases.
25. Treatment
In severely ill patients, the first priority is to protect respiration by
intubation and, if necessary, ventilation.
Anticholinesterase drugs – Inhibit cholinesterase, the enzyme
responsible for the breakdown of acetylcholine, allowing enhanced
receptor stimulation.
Edrophonium – Intravenous
Neostigmine – Intravenous, intramuscular, oral
Pyridostigmine – Oral
A muscarinic inhibitor, atropine, may be required to counter side
effects
Atropine may mask early warning symptoms of the potential life-
threatening state.
26. Steriods:
Prednisone 60 mg/day is initially used.
Deterioration may briefly occur before improvement
Immunosuppressants other than steroids
Azathioprine and cyclosporine are considered in patients
who do not respond to steroids or who require an
unacceptably high steroid maintenance dose.
27. Thymectomy
There are two indications for this:
1. When thymoma is present
2. When myasthenia is generalised and benefits of surgery
outweigh risks.
Trans-sternal is preferred to supra-sternal approach giving
better chance of total clearance.
Within 5 yrs of surgery 70% of patients are in remission.
28. Plasmapheresis
Plasma filtration removes antibodies and other circulating factors
and has short term benefit (4–6 weeks).
A plasma volume of 1.5–2 litres is exchanged 3–5 times over a 6–8
day period.
Immunoglobulin (IVIG)
May be used in place of plasmapheresis at a dose of 400 mg per kg
intravenously daily for 5 days.
Mechanism may act by blocking ACh receptors.
A positive response (75% of patients) lasts for 2–3 months.