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MG Desya Bismillah
MG Desya Bismillah
Lecturer Adviser:
dr. Donny H Hamid Sp.S
Epidemiology
MG is rarely found disease, the incidence is only about 1.7 to 21.3 per 1000.000, and
can occur all age and gender. In some research the onset of MG is influenced by gender and
age. In patients younger than 50, women predominate with a ratio of 7:3 whereas after age 50,
new cases of MG are slightly more common in men with a ratio of 3:2. The highest prevalence
is women in age 20-30, while men in age 60.
With the increasing ability of diagnosis, therapy and life expectancy, the prevalence of MG is
increasing it is about 15-179:1000.000 cases with about 10% are children and adolescents. This
risk will increase if in the family, siblings, and parents have history of MG or any other
autoimmune diseases.
Etiology
Autoimmune MG results from antibody-mediated, T cell-dependent immunologic
attack on the postsynaptic membrane of the neuromuscular junction. Abnormal neuromuscular
transmission and clinical weakness in MG result from the effects of antibodies that bind to
various epitopes of the skeletal muscle endplate region. In most cases, antibodies bind to the
main immunogenic region of the α-subunit of the AChR, though MG patients with antibodies
to MuSK exhibit clinical weakness and electrophysiologic findings that are quite similar to
MG patients with AChR antibodies. MuSK initiates aggregation of AChRs at the muscle
endplate during development, but the function of MuSK in mature skeletal muscle and the
pathophysiology of MG related to MuSK antibodies are currently unknown.
In sero-positive MG, binding of antibody to the AChR initiates autoimmune attack on the
endplate region. Subsequent damage to the postsynaptic membrane results in simplification of
the normal, highly-infolded surface that is accompanied by reduced number and density of
AChR. The functional loss of AChRs reduces the probability of successful neuromuscular
transmission following quantal release of acetylcholine by the motor nerve terminal, resulting
in clinical weakness in striated muscles.
MG and other autoimmune disorders result from the loss of tolerance to self-antigens.
T-lymphocyte tolerance to self-antigens is established in the thymus, and thymic abnormalities
are often present in MG. Thymic hyperplasia is observed in about 65% of MG patients, and
thymomas are present in about 10% of MG patients. MG patients with thymoma have more
severe and generalized weakness, higher AChR antibody titers, and more severe
electrophysiologic abnormalities. Accordingly, patients with SN and ocular MG are less likely
to have thymomas. Most thymic tumors are benign, well differentiated, and encapsulated.
Patients with MG should undergo chest computed tomography (CT) to exclude the presence of
thymoma. While thymoma resection is necessary to prevent compromise of mediastinal
structures, the benefit of thymectomy for patients with non-thymomatous MG remains
uncertain.
Pathophysiology
Clinical Presentation
Patients with generalized MG can present with weakness and fatigability of any striated
skeletal muscle group. Physical examination may reveal weakness that is generalized, apparent
only in certain muscles, or present primarily after sustained effort . The most commonly
involved muscles outside of the lids and extraocular muscles, include the facial muscles, neck
flexors, triceps, and quadriceps. The limbs are usually more affected in a proximal distribution.
Weakness of the jaw or pharyngeal muscles can lead to dysphagia, and weakness of the
diaphragm can lead to respiratory failure. On neurological examination: Reflexes,
coordination, sensation, bladder and bowel function should be unaffected in patients with
presumed MG.
In about 70% MG patient, the early symptoms are assymetrical eye, which occur in the
extraocular muscle, resulting in drooping or falling of the upper eyelid (ptosis) or double vision
(diplopia). From all the ocular types, about 50% develop in to the generalized type, weakness
that occurs in the muscle bulbar muscles and proximal muscles. While, 15% remain in the
ocular type. The severe clinical symptoms often found in the first until the third year, rarely
found perfect and permanent clinical improvement.
2. Bulbar Symptoms
Bulbar muscle involvement can be seen in 60% of patients, presenting as
painless dysarthria (impaired speech) often found in the early onset MG and
dysphagia (difficulty swallowing) appear after patient eat solid foods. patient will
find it hard to move their jaw while chewing their food, so it should be helped with
his hands. These signs occur due to weakness of palatal, facial and oropharyngeal
muscles.
Many patients with MG have a characteristic facial appearance, facial
weakness may Changes in facial expressions and flattened nasolabial fold may be
seen, giving the patient an “expressionless” appearance. Often, patients will elevate
an eyebrow by contracting the frontalis muscle in an attempt to compensate for
ptosis. Weakness of the orbicularis oris muscle may produce the characteristic
horizontal or ‘‘snarling’’ appearance with attempts to smile. Patients may also have
difficulty puffing their cheeks or pursing their lips.
4. Respiratory
Respiratory muscles. It is frequently difficult to reliably distinguish the
status of the respiratory muscles from the functional status of the lungs themselves.
However, simple observa- tion is often quite revealing. Patients with respiratory
muscle weakness due to MG often present with tachypnea and shallow breathing.
They may be anxious because of an inability to draw. a full breath. Asking patients
to inspire forcefully and loudly through the nose (inspiratory sniff) can give one a
good indication of inspiratory muscle strength. To assess expiratory muscle
function, patients should be asked to cough or clear their throat.. A weak sniff and
cough along with significant tachypnea or tachycardia are signs of clinically
important respiratory muscle weakness.
Diagnosis
The diagnosis of OMG is usually made by a combination of patient history, clinical
presentation, and other diagnostic procedures. The first suspicion of OMG should come to
mind during the case history if the patient manifests symptoms of ptosis, diplopia, and/or blur,
which increases with use of the ocular muscles, or as the day progresses. Patients with
generalized systemic MG may also manifest fatigue of the face, neck, and limbs, worsening
with activity. Brushing one’s teeth or combing hair may become prob- lematic. Head droop
and down-sloping of a smile may be noted. Variability of symptoms should further trigger
suspicion. The gold standard for diagnosis of OMG is the Tensilon test. However, there are a
number of non-invasive tests that can also be used to make the diagnosis.
Ocular myasthenia
o Patients may have diplopia at rest or it may only come out with use of the eyes
o Sustained upgaze and repeated blinking will use these muscles. Repeating eye movement
testing after this sustained upgaze or repeated blinking will exacerbate any weakness and bring
out diplopia and ptosisrespectively from use of the relevant muscles
Limb weakness
o Ask the patient to lift their arms to 90 degrees and check their shoulder abduction and
adduction. If this is equal, then ask them to move ONE ARM up and down 20 times to
fatigue these muscles
o Following this, retest shoulder abduction and adduction and compare sides
o Both abduction and adduction should now be demonstrably weaker than in the unused arm
Central/bulbar involvement
o Test the power of head/neck flexion and extension (fatigue this movement as above)
o Ask the patient to take a deep breath and count out loud as many numbers as they can. Compare
this to your own (i.e. count at the same time)
Tensilon test
Edrophonium chloride is an acetylcholinesterase inhibitor with rapid onset
(approximately 30 seconds) and short duration (approximately 5 minutes) of pharmacologic
action. Edrophonium chloride temporarily improves the safety factor of neuromuscular
transmission and may elicit improved strength in patients with abnormal neuromuscular
transmission. Edrophonium testing is considered positive when unequivocal improvement in
strength follows intravenous administration of edrophonium. Development of increased
weakness may also suggest abnormal neuromuscular transmission. The primary limitation of
edrophonium testing relates to selection of an objective muscle strength parameter for
assessment. Therefore, edrophonium testing is most useful in patients who have significant
ptosis or restricted extraocular movements that can be graded objectively. During testing, up
to 10 mg of intravenous edrophonium chloride may be administered. Because of the potential
for serious muscarinic side effects including bronchospasm and bradycardia, atropine should
be readily available. Typical muscarinic side effects include increased sweating, lacrimation,
salivation, nausea, and diarrhea. An incremental dosing schedule should be utilized with one
minute observation periods following each dose of edrophonium. If muscle strength improves
clearly within one minute following any dose increment, the test is considered to be positive
and the procedure is concluded.
Imaging
All MG patients should have computed tomography (CT) or magnetic resonance imaging
(MRI) of the thorax to screen for thymoma or thymic hyperplasia. Imaging of the mediastinum
should be repeated in the context of a MG relapse after a period of stable disease to exclude
the development of a thymoma, which can occur later in the disease course
Electrodiagnostic testing
Electrophysiological studies are performed in patients with suspected MG to confirm a defect
in neuromuscular transmission and also to exclude other diseases of the motor unit that may
confound or contribute to the clinical findings. The two principal electrophysiological tests
used to confirm a defect in neuromuscular trans- mission are repetitive nerve stimulation (RNS)
studies and single-fiber electromyography (SFEMG).
Antibodies
The presence of serum binding antibodies to human AChR is highly specific for the diagnosis
of MG. In 74% of patients with myasthenia gravis, serum antibodies to acetylcholine receptor
are present. Normal AChR binding antibody concentra- tions do not exclude the diagnosis,
even in generalized MG. Virtually all MG patients with thymoma will have elevated AChR
binding antibodies. The diagnostic specificity for MG is quite good, although increased titers
may rarely be found in autoimmune liver disease, systemic lupus, inflammatory neuropathies,
amyotrophic lateral sclerosis, as well as in patients with thymoma without MG.
Clinical Classification
The Myasthenia Gravis Foundation of America (MGFA) clinical classification divides MG
into 5 main classes and several subclasses. It is designed to identify subgroups of patients with
MG who share distinct clinical features or severity of disease that may indicate different
prognoses or responses to therapy.
Differential diagnosis
Differential diagnosis includes other disorders of the neuromuscular junction including
Lambert Eaton syndrome, botulism, congenital myasthenic syndromes, and tick paralysis. In
addition, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and variants of
AIDP affecting cranial muscles such as the Miller-Fisher and cervical-brachial-pharyngeal
variants may simulate MG, though the weakness does not have the same variability.
Mitochondrial neuromuscular disorders, particularly those featuring external ophthalmoplegia
and ptosis, may simulate MG. However, the onset of symptoms is gradual, and the weakness
does not fluctuate greatly. Motor neuron disease involving oropharyngeal weakness may
appear similar to MG, though the presence of corticobulbar features and increased fiber density
measurements on SFEMG can assist in distinguishing these entities. Finally, brainstem
ischemia may simulate the fluctuating character of MG, though unlike MG, consciousness,
balance and coordination, and sensation are often impaired.
Treatment
Cholinesterase inhibitors
Pyridostigmine bromide is the most common rst treatment which causes reduction of
acetylcholine breakdown by acetylcholinesterase inhibition. Initial doses of 30 to 60mg of
pyridostigmine every 3 to 6 hours are recommended. The maximum effectiveness is seen early
in the disease course and over time patients may develop tolerance, which may respond to dose
escalation. Single doses greater than 120 to 180mg rarely provide superior bene t and usually
only lead to greater side effects. Pyridostigmine continues to have a role in symptomatic
management
Corticosteroids
Prednisone is the first-line immunosuppressant treatment for MG. A dose of 60 to 80 mg daily
is usually recommended, but acute worsening of weakness may be observed in rst 7 to 14 days
a er treatment initiation in about half of patients. Because of this, it may be helpful to start with
a lower dose and gradually titrate up. Improvement in weakness tends to be seen within 2
weeks, and in upwards of 90% of patients within 1 month with maximum significant
improvement observed by 6 to8 weeks the biggest challenge is the numerous side effects such
as hyperglycemia, bone loss, gastric ulcers, weight gain and edema, which makes the long term
utility of this form of immune suppressant difficult to use.
Neuromuscular blocking agents (paralytics) should be used with caution when intubating MG
patients. Depolarizing agents (for example, succinylcholine) are less potent in myasthenics
because fewer functional post-synaptic AChR are available. This decrease in receptors also
results in a decrease in the safety margin or remaining AChR available for neuromuscular
transmission. Nondepolarizing agents (for example, vecuronium) have increased potency, and
reduced doses are required for paralysis
b. Noninvasive Ventilation
B. Cholinergic crisis
Cholinergic crisis results from an overdose of acetylcholinesterase inhibitors causing profound
weakness due to continuous depolarization of the postsynaptic membrane, which in turn results
in a depolarizing type of neuromuscular blockade. In general, cholinergic crisis causes other
symptoms, such as excessive salivation, cramps, diarrhea, and blurred vision. One of the
treatment modalities for myasthenia gravis is the use of acetylcholinesterase inhibitors
(AChEI) such as pyridostigmine. AChEI prevents the breakdown of ACh by inactivating
AChE. This stops the breakdown of ACh and increases its level and duration of action at the
postsynaptic membrane. Excessive use of AChEI in the treatment of a patient with MG may
precipitate a cholinergic crisis which is characterized by both muscarinic and nicotinic toxicity.
The clinical symptomatology of myasthenic crisis and cholinergic crisis are very similar. The
cholinergic crisis should always be considered in myasthenic crisis although the cholinergic
crisis is not that common in myasthenia crisis.It is important to identify which of the two
conditions is causing muscular weakness. A simple test that can be done involves giving a dose
of edrophonium, 2 mg intravenous. The medication produces clinical improvement in
myasthenic crisis but worsening of symptoms in cholinergic crisis
The diagnostic work of cholinergic crisis can pose a clinical challenge, especially for those
unfamiliar with the clinical signs and symptoms. A very detailed history taking with a thorough
physical examination is necessary. In the physical examination, particular attention should be
paid to the nervous, respiratory, cardiovascular, and gastrointestinal system as this is where the
clinical manifestation is most profound. A good mnemonic to remember is
SLUDGEM and DUMBELS for the muscarinic effect of ACh.
S- Salivation
L- Lacrimation
U -Urinary frequency
D-Diarrhea
E- Emesis
M- Miosis
U -Urinary frequency
M-Miosis
E – Emesis
L – Lacrimation
S – Salivation
Muscular weakness
Tachycardia
Hypertension
Seizures
Coma
Ataxia
Slurred speech
Prognosis
Most patients develop initial symptoms of extraocular muscle weakness with asymmetric
ptosis and diplopia. The course is frequently variable, particularly within the first year of
disease. Nearly 85% of patients with initial ocular symptoms progress to develop weakness of
bulbar and limb muscles within the first three years. Initial presentations with oropharyngeal
and limb weakness are less common. Maximum disease severity is reached within the first year
in almost two-thirds of patient. Myasthenic crisis, or respiratory failure due to myasthenic
weakness occurs in about 20% of patients, usually within the first year of illness. Myasthenic
symptoms and signs may worsen in the setting of systemic illness, particularly viral upper
respiratory infections, thyroid disease, pregnancy, increased body temperature, and exposure
to drugs that impair neuromuscular transmission.
Clinical diagnosis of cholinergic crisis can be established based on the toxidromes listed
above.
In the history taking, it is very pertinent to determine the cause of the cholinergic crises:
Medications for the treatment of myasthenia gravis or glaucoma, including
pyridostigmine
Ingestion or exposure to insecticides, pesticides, or herbicides
Exposure to nerve gas
Reversal of neuromuscular blockage
Emergency Room Management
Regardless of the etiology of cholinergic crises, the core principle in stabilization is ABC:
Airway, Breathing, and Circulation.
Airway and Breathing
Care should be taken to ensure that the airway is patent and the patient is breathing
spontaneously. Airway should be secured if there is concern for airway compromise.
Indications for advanced airway management and intubation in cholinergic crisis are :
Copious oral and nasal secretions compromising the patency of the airway
Altered mental status with a Glasgow Coma Score less than 8
Evidence of hemodynamic instability
Profound weakness of the respiratory muscles
Circulation
Vascular access should be established immediately with two large bore peripheral
intravenous access. Fluid should be started to maintain adequate circulation with continuous
pulse oximetry and monitoring of vital signs. In case of hemodynamic instability a central
venous access should be established for infusion of vasoactive medications.
In the emergency department, the primary focus on initial management is the maintenance of
airway and hemodynamic stability. If the patient is already intubated, ventilatory support
should be continued .
Inpatient Management
Inpatient care includes continued cardiopulmonary support and monitoring. Patients with
cholinergic crisis should be admitted to the intensive care unit.
Antidotes for cholinergic crisis
Two types of antidotes are used for a cholinergic crisis: atropine and oximes.
Atropine
The first antidote is atropine. It is an effective agent for the muscarinic effect of
acetylcholine. It competitively binds to the post synaptic muscarinic receptor thereby
preventing further action of ACh. Atropine dose is about 0.03- 0.05 mg/kg for pediatric and
about 2 mg for adult patients. It is recommended to give atropine until signs of atropinization
is present:
Signs of atropinization
Tachycardia
Warm, dry and flushed skin
Mydriasis
Atropine does not have any effect on the nicotinic receptors.
Oximes
For the nicotinic effect in cholinergic crisis, the antidote is a class of drugs called the
“oximes.” Examples of oximes are pralidoxime and obidoxime.