MYASTHENIA GRAVIS

By: REGINA
Lecturer Adviser: dr. BAMBANG Sp.S

History of MG

Myasthenia (Greek muscle

illness)
Gravis (Latin grave or
serious)
First description in the 17th
century
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

Definition
Myasthenia gravis is a disorder of neuromuscular
transmission, characterised by weakness and
fatiguing of some or all muscle groups. Weakness
worsening on sustained repeated exercise and
relieved by rest. This condition is a consequence of
an autoimmune destruction of the post synaptic
reseptor for acetylcholine.

Epidemiology
Frequency
Annual incidence in US- 2/1,000,000
Worldwide prevalence 1/10,000
Mortality/morbidity
Recent decrease in mortality rate due to advances in treatment
3-4% (as high as 30-40%)

Risk factors
Age > 40
Thymoma

Sex
F-M (6:4)
Mean age of onset (M-42, F-28)
Incidence peaks- M- 6-7th decade F- 3rd decade

Whos at Risk

Females 20-40
Males 60-80
Those with another AI Disease
Penicillamine users (rheumatoid med)
Enlarged Thymus or thymoma
20 in 100,000 or 2 in 1million (discrepancy)

Physiology
Neuromuscular Junction
(NMJ)
Components:
Presynaptic membrane
Postsynaptic membrane
Synaptic cleft

Presynaptic membrane
contains vesicles with
Acetylcholine (ACh) which
are released into synaptic
cleft in a calcium dependent
manner
ACh attaches to ACh
receptors (AChR) on
postsynaptic membrane
7

Anatomy of
Neuromuscular Transmission

Physiology of Neuromuscular
Transmission

Pathogenesis

Chemicals messengers, called neurotransmitters, fit

precisely into receptor sites on your muscle cells. In
myasthenia gravis, certain receptor sites are blocked
or destroyed, causing muscle weakness.

Pathogenesis

MG Damages the Muscle Endp

A.

B.

NT

NT

What is happening in the immune

system in people with MG?
T
T
APC

Anti-AChR
Abs

B
Plasma
Plasma cell
cell

T
Nerve Terminal

AChR
MuSK

Ca++

Ca++

Rapsyn
AChase
ACh
Voltage-gated
Na+ channel
Voltage-gated
Ca+ channel

AChR
MuSK

Postsynaptic membrane
Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are caused by autoantibodies directed
against the acetylcholine receptor on the postsynaptic muscle membrane.22 Anti-AChR antibodies bind to the AChR to cause
receptor internalization and degradation, as well as complement-mediated lysis of the postsynaptic membrane and consequent loss
of functional receptors

The Thymus Gland and the

Origin of MG
Thymic
Thymic
hyperplasia
hyperplasia
In patients with thymoma, the developmental process of T-lymphocytes in
thymoma is different from the one in the normal thymus. Particularly, the
mechanism of removing T-lymphocytes that may react to autoantigens
(including acetylcholine receptor ) may be lacking in thymoma. This may be
related to the onset of myasthenia gravis in thymoma patients.
We know many examples of bone marrow transplantation-related myasthenia
gravis.
The mechanism of bone marrow transplantation-related myasthenia gravis is
similar to that in thymoma associated myasthenia gravis. Both are induced by
nonspecific autoreactive lymphocytes.
For those patients without thymoma, the onset of myasthenia gravis is totally
unknown.
These patients have abnormality in the thymus, namely, germinal centers.
However, whether germinal center formation is the cause or result of
myasthenia gravis is controversial.
The target of the autoreactive antibody, acetylcholine receptor , may be
present in the thymus. But it is not certain whether the amount of
acetylcholine receptor in the thymus is sufficient to activate the developping
lymphocytes in the thymus.

AChR

Thymoma
Thymoma

Tumor cell

AChR
AChR

How is MG diagnosed?

Clinical features
Tensilon test
Antibody tests
Electrical tests

Clinical features of MG
Muscle weakness - fluctuating
Fatigue with muscle use
Double vision, droopy eyelids, trouble
swallowing/chewing
Facial weakness
Shortness of breath
No pain, numbness

CLINICAL PRESENTATION

MUSCLE
STRENGTH
Ocular muscle
weakness
Facial muscle weakness
Bulbar muscle
Bulbar
weakness
Muscles
Limb muscle weakness
Respiratory weakness

1. OCULAR MUSCLE WEAKNESS

ASYMMETRIC
Usually affects more than one
extraocular muscle and is not
limited to muscles innervated by
one cranial nerve
Weakness of lateral and medial
recti may produce a pseudo
internuclear opthalmoplegia
Ptosis is caused by Levator
palpebrae weakness
Sustained upward gaze for
30 seconds
Diplopia is very common
Lid-twitch sign, Repeated
ocular versions
Bright sunlight aggravate the
ocular signs and COLD
improves them

2. BULBAR MUSCLE WEAKNESS

Bulbar muscle
weakness( more in Anti MuSK
Ab positive cases)
Palatal muscles

Nasal voice, nasal

regurgitation
Chewing may become difficult
Severe jaw weakness may
cause jaw to hang open
Swallowing may be difficult
and aspiration may occur with
fluidscoughing and choking
while drinking

Neck muscles

Neck flexors affected more

than extensors

3. LIMB MUSCLE WEAKNESS

Upper limbs more common than lower limbs
Proximal > than distal muscles
Usually asymmetric weakness

Upper
Extremities
Deltoids
Wrist extensors
Finger
extensors
Triceps >
Biceps

Lower Extremities
Hip flexors (most common)
Quadriceps
Hamstrings
Foot dorsiflexors
Plantar flexors

4. RESPIRATORY MUSCLE WEAKNESS

Weakness of the intercostal
muscles and the diaphragm
may result in CO2 retention
due to hypoventilation
May cause a neuromuscular
emergency

Weakness of pharyngeal
muscles may collapse the
upper airway
Monitor negative inspiratory
force, vital capacity and tidal
volume
Do NOT rely on pulse oximetry
Arterial blood oxygenation may
be normal while CO2 is retained

5. Myasthenic crisis
Defined as respiratory
failure requiring
mechanical ventilation
The respiratory
symptoms, in conjunction
with severe bulbar
symptoms, can culminate
in so-called myasthenic
crisis
This complication occurs
in about 1520% of
patients with MG and
may be precipitated by
infection or aspiration

Classifications

I. Ocular myasthenia (15 to 20 percent)

II. A. Mild generalized myasthenia with slow progression, no crises, drugresponsive (30 percent)
II. B. Moderately severe generalized myasthenia; severe skeletal and bulbar
involvement but no crises, drug response less than satisfactory (25
percent)
III. Acute fulminant myasthenia; rapid progression of severe symptoms
with respiratory crises and poor drug response, high incidence of
thymoma, high mortality (15 percent).
IV. Late severe myasthenia; symptoms same as III, but resulting from
steady progression over 2 years from class I to class II (10 percent).

Diagnosis
Physical Examination
1. Cranial nerve signs and symptoms:
Ocular involvement produces ptosis
and muscle paresis.
Weakness of jaw muscles allows the
mouth to hang open
Weakness of facial muscles results in
expressionless appearance
On smiling, buccinator weakness
produces a characteristics smile
(myasthenia snarl)

2. Bulbar involvement may

result in:
Dysarthric, dysphonic
speech and dysphagia
Nasal regurgitation of fluids
or nasal quality to speech

3. The demonstration of
fatiguing :
- Simpson test
- Cogans lid twitch sign
- Blowing out cheeks
against pressure
- A counting test 100:
Counting as far as
possible in one breathe

4. Limb and trunk signs and symptoms

Weakness of neck muscles may result in lolling of
the head. Proximal limb muscles are preferentially
affected. Fatigue may be demonstrated by
movement against a constant resistance.
Limb reflexes are often hyperactive and fatigue on
repeated testing.
Muscle wasting occurs in 15% of cases.

Diagnostic Studies

Differential Diagnosis
For generalized MG the differential diagnosis
includes Lambert-Eaton myasthenic syndrome, botulism,
and myopathy
For ocular myasthenia alternative diagnoses include
progressive external ophthalmoplegia, thyroid disease,
and oculopharyngeal muscular dystrophy
For bulbar predominant myasthenia gravis Motor
neuron disease, brainstem stroke, diphtheria, and
botulism

Differential Diagnosis

Treatment

The treatment of this disease involves the careful use

of two groups of drug-anticholinesterases and
immunosuppresants including corticosteroids and in
special acute circumstances, plasma exchange and
intravenous immunoglobulin, an elective thymectomy is
appropriate in many patients as discussed below

Treatment

AChE inhibitors
Immunomodulating therapies
Plasmapheresis
Thymectomy
Important in treatment, especially if thymoma
is present

39

Treatment
AChE inhibitor

Immunomodulating therapies
Prednisone
Pyridostigmine bromide
Most commonly used corticosteroid in
US
(Mestinon)
Significant improvement is often seen
Starts working in 30-60
after a decreased antibody titer which
minutes and lasts 3-6 hours
is usually 1-4 months
Individualize dose
No single dose regimen is accepted
Adult dose:
Some start low and go high
60-960mg/d PO
Others start high dose to achieve
a quicker response
2mg IV/IM q2-3h
Clearance may be decreased by
Caution
estrogens or digoxin
Check for cholinergic crisis
Patients taking concurrent diuretics
Others: Neostigmine Bromide
should be monitored for hypokalemia
40

Treatment
Behavioral modifications
Diet
Patients may experience difficulty chewing and
swallowing due to oropharyngeal weakness
If dysphagia develops, liquids should be thickened
Thickened liquids decrease risk for aspiration
Activity
Patients should be advised to be as active as possible
but should rest frequently and avoid sustained activity
Educate patients about fluctuating nature of
weakness and exercise induced fatigability
45

 Myasthenic crisis
Rarely at the initial presentation
Known MG may reach a crisis
Defined as sudden worsening of respiratory
function and/or profound
muscle weakness
Being a neurologic emergency
Causes: concurrent infection, medications,
drug withdrawal

Complications of MG
Respiratory failure
Dysphagia
Complications secondary to drug
treatment
Long term steroid use
Osteoporosis, cataracts, hyperglycemia, HTN
Gastritis, peptic ulcer disease
Pneumocystis carinii
47

Prognosis
Untreated MG carries a
mortality rate of 25-31%
Treated MG has a 4%
mortalitiy rate
40% have ONLY occular
symptoms
Only 16% of those
with occular symptoms
at onset remain
exclusively occular at
the end of 2 years

Long-term outlook better

for children than adults
Life expectancy slightly
reduced
Most favorable outcome for
bulbar weakness
Drug free remissions
possible with thymectomy
Death rate reduced from
30% to <5% with
pharmacotherapy and
surgery
48

References
1. Delisa, S. A., Goans, B., Rehabilitatoin Medicine Principles and Practice, 1998,
Lippencott-Raven
2. Kimura, J., Electrodiagnosis in Diseases of Nerve and Muscle, F.A.Davis
Company, Philadelphia
3. Rosenberg, R. N., Comprehensive Neurology, 1991, Raven Press Ltd
4. Osullivan, Schmidtz, Physical Medicine and Rehabilitation Assessment and
Treatment, pg. 151-152
5. Grabois, Garrison, Hart, Lehmke, Neuromuscular Diseases, pgs. 1653-1655
6. Shah, A. K., www.emedicine.com, Myasthenia Gravis, 2002, Wayne State
University
7. Sidharta Priguna dan Mardjono Mahar, 2006. Neurologi Klinis Dasar. Jakarta.
Penerbit Dian Rakyat. 348
8. Godoy D, Mella L, Masatti L. The myasthenic patient in crisis: an update of the
management in neurointensive care unit. Arq Neuropsiquiatr 2013;71 (9-A): 627639
9. Shah, A. K., www.emedicine.com, Myasthenia Gravis, 2002, Wayne State
University
10.
Grabois, Garrison, Hart, Lehmke, Neuromuscular Diseases, pgs. 1653-1655
49