DIAGNOSIS AND MANAGEMENT OF MYASTHENIA GRAVIS

Lecturer Adviser:
dr. Donny H Hamid Sp.S

Desya Billa Kusuma Anindhira

1102014070

Clinical Science of Neurology

General Hospital Pasar Rebo East Jakarta
2018
Definition
Myasthenia Gravis (MG) is a chronic autoimmune disease which characterized with fluctuate
weakness and fatigue of the extrinsic ocular muscles (EOMs) . The symptoms usually progress
to the other bulbar muscles and limb muscles, resulting in generalized MG. The muscle
weakness will worsen with activities and improve with rest. Myasthenia Gravis is caused by
the presence of autoantibody at the post synapse membranes in the neuromuscular-junction.
Autoantibody that most commonly found in the serum of MG patient is the antibody of
acetylcholine receptor (AChR) and other also include the muscle-specific kinase (MuSK) and
low density lipoprotein receptor-related protein (LRP4).

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.

Anatomy and Physiology of the Neuromuscular Junction

There are two types of synapses: electrical and chemical. At an electrical synapses two
cells communicate with electrical current between them. While, at a chemical synapses two
cells communicate with an action potential at the pre-synaptic neuron which then will release
chemical messenger which transmits signals across a chemical synapse called
neurotransmitter. The neurotransmitter will diffuse to the extracellular synaptic space, and the
neurotransmitter will bind with the receptor on the post-synaptic neuron.
Neuromuscular Junction is a specialized chemical synapse between the axon of a motor
neuron and a somatic muscle fiber. This synapse allows the process of transmitting signals
from a motor axon to the motor neuron it innervates. Each motor neuron in brainstem or spinal
cord will give action potential to the axon that branched distally to provide a single nerve
terminal to each muscle fibers it innervates. A single motor neuron will innervates one muscle
fibers, or a single motor neuron innervates several muscle fibers. But there is an exception
within the extraocular muscle which single muscle may receive multiple innervation. This may
play role in the increased of the susceptibility of neuromuscular diseases, such as Myasthenia
Gravis.
When the action potential propagated by the motor neuron reach the nerve terminal,
this will initiate depolarization that opens the calcium canals in the pre-synaptic membrane.,
allowing an influx of calcium that results in a release of acetylcholine from the presynaptic
terminal. The acetylcholine diffuses across the synaptic cleft and binds to acetylcholine
receptors (AchR) on the postsynaptic membrane. The bond between ACh and
AChR will allows sodium to enter and depolarize the muscle cell membrane, if the
depolarization reach a certain threshold value called the firing level, then there will be potential
action on the muscle cell, this action potential will propagates and will lead to muscle
contraction.
The extracellular matrix of the synaptic cleft is a complex collection of proteins that
regulate the synthesis of acetyl-choline esterase (AChE). Once released from the synaptic
vesicles, diffusion of ACh across the cleft is rapid because of the small distance to cross and
the high diffusion rate of ACh. AChE is concentrated in the basal lamina of the post-synaptic
membrane, The rest of Ach still attached to its receptors will then be hydrolyzed by ACHe.
ACh will be broken into choline and lactic acid, and choline will enter the pre-synapse
membrane to form another Ach. This Hydrolysis process occur to prevent continuously
potential action that will lead to nonstop muscle contraction.

Ethiopathogenesis

Two major components implicated in MG pathogenesis are acetylcholine receptors

(AChR) and muscle-specific tyrosine kinase receptors (MuSK), both located on the
postsynaptic membrane. Autoimmune antibodies to AChR (AChR-Ab) are detected in 70% to
90% of MG patients while MuSK (MuSK-Ab) is seen in 5% to 8% of MG patients. The anti-
AChR antibodies reduce the number of effective receptors to approximately one-third of the
normal number by a number of mechanisms. AChR antibodies bind to extracellular domains
of the receptor causing disruption of the signal transduction. Autoimmune MG results from
antibody-mediated, T cell-dependent immunologic attack on the postsynaptic membrane of the
neuromuscular junction. The autoantibodies fix onto Ach receptors sites, blocking the binding
of acetylcholine. Eventually the antibody action destroys receptor sites. This loss of AChR
sites causes diminished transmission of the nerve impulse across the neuromuscular junction
and decreased muscle depolarization. Symptomatic induviduals without anti AChR
andtibodies may have antibodies against muscle specific kinase (MuSK) with similar
symptoms.
The role of MuSK Antibodies in the pathogenesis of MG is still unclear. MuSK protein
plays a critical role in autoregulating the concentration of the AChR on post-synaptic
membrane, In 15% MG patient autoantibodies are directly against the MuSK protein,l,MuSK
protein gives signal to the post-synaptic membrane to control the trafficking of AChR at NMJ
when the MuSK become disfungsional the autoregulation of AChR in the post-synaptic
membrane are impaired.
Low-density lipoprotein receptor-related protein 4 (LRP4) is crucial membrane protein
in the development and function of neuromuscular junctions and motor neurons. And, it is
currently known myasthenia gravis (MG) is caused by antibodies to the acetylcholine receptor
(AChR), muscle-specific kinase (MuSK), and LRP4. MuSK and LRP4 are coreceptors for
agrin in the signaling pathway that causes clustering of AChR. We demonstrated anti-LRP4
antibodies played a key role in MG. LRP4 is essential for maintaining the structural and
functional integrity of the neuromuscular junction and that loss of muscle LRP4 in adulthood
alone is sufficient to cause myasthenic symptoms. MG with anti-LRP4 antibodies is considered
a rare subtype of MG, however, LRP4 autoantibodies have been recently detected in some
motor neuron disease patients, and LRP4 is required for presynaptic and postsynaptic
differentiation.
MG may either manifest as an autoimmune disease with distinct immunogenetic
characteristics or as a paraneoplastic syndrome associated with tumors of the thymus but only
rarely with other malignancies . Thymic abnormalities are clearly associated with myasthenia
gravis but the nature of the association is uncertain. Ten percent of patients with myasthenia
gravis have a thymic tumor and 70% have hyperplastic changes (germinal centers) that indicate
an active immune response. These are areas within lymphoid tissue where B-cells interact with
helper T-cells to produce antibodies. Because the thymus is the central organ for
immunological self-tolerance, it is reasonable to suspect that thymic abnormalities cause the
breakdown in tolerance that causes an immune-mediated attack on AChR in myasthenia gravis.
The thymus contains all the necessary elements for the pathogenesis of myasthenia gravis:
myoid cells that express the AChR antigen, antigen presenting cells, and immunocompetent T-
cells. Thymus tissue from patients with myasthenia gravis produces AChR antibodies when
implanted into immunodeficient mice. However, it is still uncertain whether the role of the
thymus in the pathogenesis of myasthenia gravis is primary or secondary. Most thymic tumors
in patients with myasthenia gravis are benign, well-differentiated and encapsulated, and can be
removed completely at surgery. It is unlikely that thymomas result from chronic thymic
hyperactivity because myasthenia gravis can develop years after thymoma removal and the
HLA haplotypes that predominate in patients with thymic hyperplasia are different from those
with thymomas. Patients with thymoma usually have more severe disease, higher levels of
AChR antibodies, and more severe EMG abnormalities than patients without thymoma. Almost
20% of patients with myasthenia gravis whose symptoms began between the ages of 30 and 60
years have thymoma; the frequency is much lower when symptom onset is after age 60.

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.

clinical symptoms of MG:

1. Ocular symptoms
The pattern of extraocular muscle weakness in MG is typically asymmetric
and not isolated to the distribution of a single cranial (III, IV, VI) nerve. The pattern
of weakness may fluctuate and change even during the course of a single
examination. The medial rectus muscle is most frequently affected, followed by the
superior and lateral rectus muscles. Rarely, weakness may be isolated to the lateral
recti. Assymetric ptosis and diplopia are common found in ocular symptoms. ptosis
which is one of the symptoms of ocular paralysis of the nerve, is often a major
complaint of patients with myasthenia gravis. Even in myasthenia gravis, clearly
 the levator muscle of the palpebra is paralyzed, there are times when the ocular
muscles are still moving normally. But in the advanced stages of ocular muscle
paralysis both sides will complement ptosis.
Diplopia, secondary to paresis of extraocular muscles, is the second most
frequent initial symptom of ocular and generalized MG. Like ptosis, the oph-
thalmoplegia worsens at the end of the day or upon exertion. It may mimic any
disorder of eye movements or exhibit complete external ophthalmoplegia. Reduced
accommodative amplitudes, facility, and near point of convergence stamina may
also be associated in MG patients.

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.

3. Neck and limbs

Neck flexor and extensor muscles are often weak in MG. Though the neck
flexors are usually weaker, a "dropped head syndrome" due to neck extensor
muscle weakness may occur. Although painless weakness is the rule in MG,
patients with neck extensor weakness may experience posterior neck myalgias.
Finger and wrist extensors and shoulder abductor muscles are most likely
to be affected in the upper limb. In the lower extremity, the foot dorsiflexors and
hip flexors are most frequently involved. Weakness is usually relatively sym-
 metric, but may be asymmetric and even focal. Hand muscles, particularly finger
extensors, appear to be involved more frequently than distal leg and foot muscles.

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 observation 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.

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.

/
 Diagnosis
The diagnosis of MG is usually made by a combination of patient history, clinical presentation,
and other diagnostic procedures. The first suspicion of MG 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 problematic. Head droop and down-sloping of a smile
may be noted. Variability of symptoms should further trigger suspicion. The gold standard for
diagnosis of MG 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 ptosis respectively 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 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.

Ice pack test

A quick method to distinguish ptosis due to MG from other causes is the ice pack test.
An ice cube is placed over the drooping eyelid for about two minutes, and if there is
improvement in the ptosis, it suggests a neuro muscular transmission disorder. Results pooled
from six studies gave this test a sensitivity of 89 percent and a specificity of 100 per cent.

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).

Repetitive Nerve Stimulation

Nerve conduction studies can test both the sensory and the motor nerves, in the context of MG
generally only the motor nerves are examined. An electrical stimulus (shock) is applied to the
skin overlying the nerve, the nerve then activates and sends the signal to the muscle supplied
by that nerve. The size of the muscle response and the time that the nerve signal takes to get
there is recorded from a separate set of electrodes on the skin over the muscle.
In MG repetitive closely timed stimuli will often produce progressively smaller or weaker
responses in the muscle recording electrodes. This is called Decrement of the Compound
Muscle Action Potential (CMAP) in the Repetitive Stimulation Test. An example of decrement
on repetitive stimulation can be seen below, with progressive decline in size (and therefore
power) in the first four muscle responses. This is the electrical, objective equivalent of the
fatigue that most patients with MG experience.

In some instances an electromyogram (EMG) will also be performed, particularly if an

alternative diagnosis is being considered. An EMG involves placing a very tiny electrode
needle into the muscles, and the muscle will then be examined both with the patient relaxing
the muscle and with the patient activating the muscle.

Single-Fiber Electromyography (SFEMG)

SFEMG is the most sensitive nerve test of neuromuscular transmission and shows increased
jitter in some muscles in almost all patients with myasthenia gravis. This test use a selective
recording technique in which a specially needle is used to identify and record action potentials.
Jitter can be thought of as a measure of the fatigability within a microscopic single motor unit
itself, rather than within the muscle as a whole which is tested with repetitive stimulation. The
tiny needle is actually inserted within a single motor unit. Jitter is greatest in weak muscles but
may be abnormal even in muscles with normal strength. Increased jitter is a nonspecific sign
of abnormal neuromuscular transmission and can be seen in other motor unit diseases.
Therefore the finding of increased jitter does not definitely mean that MG is present. Normal
jitter in a weak muscle excludes abnormal neuromuscular transmission as the cause of
weakness,but SFEMG demonstrates increased jitter in virtually all patients with MG if
appropriate muscles are tested.

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 concentrations 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.

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 first 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 benefit and usually
only lead to greater side effects. Pyridostigmine continues to have a role in symptomatic
management. form can also be used mostly at night time.

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 first 7 to 14
days after 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.

Non-steroidal immune suppressants

Use of azathioprine as a steroid-sparing agent is supported by good quality evidence and allows
for tapering off of the prednisone. Its mode of action is through purine synthesis inhibition
leading to inhibition of the dividing T and B lymphocytes. Azathioprine is usually provided at
a dose of 2 to 3 mg/kg divided into two or three doses per day. A treatment response takes over
12 months usually. When azathioprine is not tolerated or if the MG remains difficult to control,
alternative immunosuppressants can be used including methotrexate (commonly used second
line), mycophenolate mofetil or tacrolimus.

Rapid short-term immunomodulation

Intravenous immunoglobulin (IVIG) or plasma exchange (PE) is used in acute severe
exacerbations of generalised MG or to optimise muscle strength prior to surgery. IVIG and PE
are equal first-line treatments because they have similar efficacy. However, because IVIG is
easier to administer and associated with fewer adverse events than PE, the former is often
preferred. Two randomised controlled trials comparing IVIG to PE showed no significant
differences between the two treatments in acute exacerbation of MG or in chronic moderate-
to-severe MG. Both treatments are well- tolerated, and the duration of e ect is comparable.
Either treatment may be o ered to patients depending on availability of resources.

Long-term immunomodulation
Thymectomy is always indicated in patients with a thymoma because of its malignant potential.
Thymectomy within the first three years of diagnosis may lead to a better response. The proce-
dure is commonly restricted to patients under the age of 60-65 years because older patients
usually have an atrophic thymus. Anti-MuSK antibody-positive patients tend to have a poorer
response, probably explained by the lack of typical thymus pathology in these patients.

Emergency Aspect of Myasthenia Gravis

A. Myasthenic crisis
Definition
Myasthenic crisis is a complication of myasthenia gravis characterized by worsening
of muscle weakness, resulting in respiratory failure that requires intubation and mechanical
ventilation. Advances in critical care have improved the mortality rate associated with
myasthenic crisis. This article reviews the epidemiology of myasthenic crisis and discusses
patient evaluation. Therapeutic options including mechanical ventilation and pharmacological
and surgical treatments are also discussed.
Myasthenic crisis can involve the upper airway muscles, respiratory muscles, or a combination
of both muscle groups. Both inspiratory and expiratory respiratory muscles can be affected,
manifesting as dyspnea. Inspiration is performed primarily by the diaphragm and external
intercostal muscles and secondarily by the sternocleidomastoid and scalene muscles. Although
expiration is primarily passive, the abdominal and internal intercostal muscles can be recruited
to assist. In MG with AChR antibodies, muscle weakness tends to initially affect the intercostal
and accessory muscles and then the diaphragm.

Respiratory Management of Myasthenic Crisis

a. Intubation and Mechanical Ventilation
Respiratory support is imperative in the management of myasthenic crisis. Two-thirds
to 90% of patients with myasthenic crisis require intubation and mechanical ventilation. Over
20% of patients require intubation during evaluation in the emergency department, and almost
60% are intubated after admission to an intensive care unit. Elective intubation of a myasthenic
patient with impending respiratory failure is favored over emergent intubation. Once intubated,
patients should be placed on an assisted ventilator setting with tidal volumes of 8-10 cc/kg
ideal body weight and pressure support of 8-15 cm H2O to prevent atelectasis and to minimize
the work of breathing. The degree of support required is ultimately patient dependent.
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

Noninvasive ventilation (NIV) may be used to prevent intubation or reintubation of

patients in myasthenic crisis.22 With bilevel positive airway pressure (BiPAP), positive
pressure is applied during both phases of respiration, enhancing airflow and alleviating the
work of breathing during inspiration and preventing airway collapse and atelectasis during
expiration
Initial use of NIV is associated with a shorter duration of ventilatory support. Patients treated
initially with NIV require ventilatory support for a median of 4 days versus 9 days in those
patients initially intubated. In addition, these patients spend one-third less time in the ICU and
in the hospital.

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.

Clinical Findings Related to Stimulation of Muscarinic Receptors

S- Salivation

L- Lacrimation

U -Urinary frequency

D-Diarrhea

G- Gastrointestinal cramping and pain

E- Emesis

M- Miosis

Another mnemonic that is commonly used for symptoms is "DUMBELS."

D- Diaphoresis and Diarrhea

U -Urinary frequency

M-Miosis

B-Bronchospasm and Bronchorrhea

E – Emesis

L – Lacrimation

S – Salivation

Clinical Findings Related to Stimulation of Nicotinic Receptors

 Muscular weakness

 Muscular fatigue and fasciculation

 Respiratory muscle weakness

  Tachycardia

 Hypertension

Clinical Findings Related to Stimulation of the Central Nervous System

 Seizures

 Coma

 Ataxia

 Slurred speech

 Agitation and restlessness

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.
Conclusion

MG is the best characterised autoimmune disease with well-defined pathogenetic antibodies

that impair function through the destruction and inhibition of muscle cell AChR. The external
causes for MG are totally unknown, apart from those 10–15% of patients with a paraneoplastic
condition linked to thymic neoplasia.
Advances in our understanding of the pathophysiology of MG have led to more effective
treatments for this condition. Earlier disease recognition combined with prompt appropriate
treatment are key factors in improving the prognosis of MG. Therefore, the need to educate
and improve disease awareness is important in the diagnosis and management of this eminently
treatable neurological disorder.
MC is a severe and life-threatening neurological condition characterized by generalized muscle
weakness with respiratory or bulbar compromise that require ventilatory support. It can be the
debut form of MG, so the diagnosis should be confirmed following a standardized protocol.
Evaluation of bulbar and respiratory functions is imperative. The cornerstones of the treatment
are correct ventilatory management, search and correction of predisposing factors, specific
immunotherapy (PE, IVIg), avoiding systemic complications, and planification of long-term
treatment (immunosupressors).
The majority of patients with MC require endotracheal intubation and mechanical ventilation.
Thymectomy should be evaluated. With modern intensive care, the outcomes are excellent with
mortality near to 5% attribuited principally to comorbidities, cardiac complications, or
pulmonary embolism.

References
Ahmed A and Milind KDO. Myasthenia Gravis: An Updated Review. Austin Journal of
Musculoskeletal Disorder. 2016; 3(2): 1032.

A Chaudhuri and P Behan. Myasthenic crisis: An International Journal of Medicine. 2009;

102:97-107

Pasnoor M, Wolfe GI, Nations S, et al. Clinical findings in MuSK-antibody positive

myasthenia gravis: a U.S. experience. Muscle Nerve 2010; 41:370–374.

Giraud M, Vandiedonck C, Garchon HJ. Genetic factors in autoimmune myasthenia gravis.

Ann NY Acad Sci 2008;1132:180-92.

Wendell L. C., Levine J. M. Myasthenic crisis. The Neurohospitalist. 2011;1(1):16–22. doi:

10.1177/1941875210382918.

Vaphiades MS. Bhatti MT, Lesser RL. Ocular myasthenia gravis. Curr Opin Ophthalmol.
2012;23:537- 542.

N. Sommer, N. Willcox, G. C. Harcourt, J. Newsom-Davis.Myasthenic thymus and thymoma

are selectively enriched in acetylcholine receptor-reactive T cells. Ann Neurol. 1990
Sep; 28(3): 312–319. doi: 10.1002/ana.410280303

Bonovich,D. Myasthenia Gravis: Critical Care Secrets. 2007, Pages 414–418

Hart I.K., Sharshar T., Sathasivam S. Immunosuppressant drugs for myasthenia gravis. J.
Neurol. Neurosurg. Psychiatry. 2009;80:5–6

Juel V, Massey J. Myasthenia gravis: Orphanet Journal of Rare Disease. 2007: 2:44

Meriggioli MN. Myasthenia gravis: immunopathogenesis, diagnosis, and

management. Continuum: Lifelong Learning in Neurology. 2009;15:35–62
Marsteller, H.B. 1988. The first American case of myasthenia gravis. Arch. Neurol. 45:185–7.

Heldal AT, Owe JF, Gilhus NE, et al. Seropositive myasthenia gravis; a nationwide
epidemiologic study. Neurology 2009; 73: 150–51