Myasthenia Gravis

“Descending Paralysis”
(NMJ –AI destruction of AChR)
 Myasthenia Gravis

skeletal (voluntary) muscles disorder

characterized by weakness and easy fatigability
due to autoimmune destruction of the AChR in
the postsynaptic membrane of the
NMJ

Progressive muscle paralysis without

sensory loss or atrophy.
• Neuromuscular Junction (NMJ)
– Components:
• Presynaptic membrane
• Synaptic cleft
• Postsynaptic membrane
– 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
• Neuromuscular Junction (NMJ)
– The Acetylcholine receptor (AChR) is a sodium
channel that opens when bound by ACh
• There is a partial depolarization of the postsynaptic
membrane and this causes an excitatory postsynaptic
potential (EPSP)
• If enough sodium channels open and a threshold
potential is reached, a muscle action potential is
generated in the postsynaptic membrane
 Background
• Acquired autoimmune disorder
• Clinically characterized by:
– Weakness of skeletal (voluntary) muscles
– Fatigability on exertion.
• First clinical description in 1672 by Thomas
Willis.
Grade Levels of MG:
classification by disease severity
Grade I: Focused and specific such as Ocular Myasthenia Gravis
(weakness of the eye muscles)
Grade II a: Generalized mild weakness
II b: Generalized moderate weakness
Grade III: Generalized severe weakness
Grade IV: Myasthenia Crisis
a severe exacerbation of the disease an depletion of ACh
receptors at the NMJ causing severe muscle weakness,
respiratory insufficiency and SOB , extreme
difficulty swallowing, may cause quadriplegia or
quadriparesis (incomplete paralysis).
Generalized autoimmune MG
Myasthenia Gravis has several courses:

1. periodic remissions
2. A slowly progressive course
3. A rapidly progressive course
4. A fulminating course
(exploding in a sudden manner)
 Etiology
– Thymoma
 it gives an incorrect
instructions to developing
immune cells, ultimately
resulting in autoimmunity
and the production of the
AChR antibodies, setting
the stage for the attack on
the NMJ.
Etiology
 Etiology
Virus
 Etiology
Drugs
• Antibiotics • Procainamide
(Aminoglycosides, • Verapamil
ciprofloxacin, • Quinidine
ampicillin,
• Chloroquine
erythromycin)
• B-blocker • Prednisone
(propranolol) • Timolol
• Lithium • Anticholinergics
• Magnesium SO4
 Etiology

Disease without
recognizable cause
as of spontaneous
origin.

?
 Pathophysiology
• In MG, antibodies are directed toward the
acetylcholine receptor at the neuromuscular
junction of skeletal muscles
• Results in:
– Decreased number of nicotinic AChR at the
motor end-plate
– Reduced postsynaptic membrane folds
– Widened synaptic cleft
Etiology : IgG antibody interact Reduced receptor by
AChR at the NMJ. blocking,
Ideopathic
degradation, damage
Thymoma Reduced AChR
Virus (HSV) density
Autoimmune
Decrease binding of
ACh to AChR

Diminished
transmission of nerve
impulses at NMJ
Decrease amplitude
Of AP
Failure in muscle fiber
contraction
Weakness muscle
(voluntary)
Grade Levels of MG:
Classification by Severity

Grade I: Focused and specific such as Ocular MS

(weakness of the eye muscles)
Grade II a: Generalized mild weakness
II b: Generalized moderate weakness
Grade III: Generalized severe weakness
Grade IV: Myasthenia Crisis a severe exacerbation of the disease
and depletion of ACh receptors at the NMJ causing severe
muscle weakness, respiratory insufficiency and SOB, extreme
difficulty swallowing may cause quadriplegia or quadriparesis
(incomplete paralysis).
Generalized autoimmune MG
Myasthenia gravis has several
courses:
1. Periodic remissions
2. Slowly progressive course
3. Rapidly progressive course
4. Fulminating course
(exploding in a sudden manner)
 
 Clinical presentation

• Ocular muscle
weakness
 Clinical presentation
• Occular 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
pseudointernuclear opthalmoplegia
– Limited adduction of one eye with nystagmus of the
abducting eye on attempted lateral gaze
– Ptosis caused by eyelid weakness
– Diplopia is very common

Risk for Eye Infection r/t exposure of cornea

 Clinical presentation
• Facial muscle weakness is almost
always present
– Ptosis and bilateral facial muscle weakness
– Sclera below limbus may be exposed due to
weak lower lids

Altered body image r/t changes in anatomical contour

of the face & neck
 Clinical presentation
• Basic physical exam findings
– Muscle strength testing
– Recognize patients who may develop
respiratory failure (i.e. difficult breathing)
– Sensory examination and DTR’s are normal
 Clinical presentation

• Bulbar muscle weakness

– 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 fluids—coughing and choking while
drinking
– Neck muscles
• Neck flexors affected more than extensors
 Clinical presentation
• Respiratory muscle weakness
– Weakness of the intercostal muscles and the diaghram 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

Ineffective breathing pattern r/t collapse of upper airway

Ineffective airway clearance r/t inability to cough.

 Clinical Presentation
• Fluctuating weakness increased by exertion
– Weakness increases during the day and
improves with rest
• Extraocular muscle weakness
– Ptosis is present initially in 50% of patients and
during the course of disease in 90% of patients
• Head extension and flexion weakness
– Weakness may be worse in proximal muscles
 Clinical presentation
• Progression of disease
– Mild to more severe over weeks to months
• Usually spreads from ocular to facial to bulbar to truncal and
limb muscles
• Often, symptoms may remain limited to EOM and eyelid
muscles for years
• The disease remains ocular in 16% of patients
• Remissions
– Spontaneous remissions rare
– Most remissions with treatment occur within the first three
years
 Clinical presentation

• Limb muscle weakness

– Upper limbs more common than lower limbs

Upper Extremities Lower Extremities

Deltoids Hip flexors (most common)
Wrist extensors Quadriceps
Finger extensors Hamstrings
Triceps > Biceps Foot dorsiflexors
Plantar flexors
 Clinical presentation
• Co-existing autoimmune diseases
– Hyperthyroidism
• Occurs in 10-15% MG patients
– Exopthalamos and tachycardia point to hyperthyroidism
– Weakness may not improve with treatment of MG alone in
patients with co-existing hyperthyroidism
– Rheumatoid arthritis
– Scleroderma
– Lupus
 Work-up
• Electrodiagnostic studies
– Repetitive nerve stimulation
– Single fiber electromyography (SFEMG)

– SFEMG is more sensitive than RNS in MG

 Electrodiagnostic studies:
Repetitive Nerve Stimulation

• Low frequency RNS (1-5Hz)

– Locally available Ach becomes depleted at all NMJs
and less available for immediate release
• Results in smaller EPSP’s
 Electrodiagnostic studies:
Repetitive Nerve Stimulation
• Patients w/ MG
– AchR’s are reduced and during RNS EPSP’s
may not reach threshold and no action
potential is generated
» Results in a decrease in the
compound muscle action potential
» Any decrement over 10% is
considered abnormal
» Should not test clinically normal
muscle
» Proximal muscles are better tested
than unaffected distal muscles
 Repetitive nerve stimulation
• Most common employed stimulation rate is
3Hz
• Several factors can affect RNS results
– Lower temperature increases the amplitude of
the compound muscle action potential
• Many patients report clinically significant
improvement in cold temperatures
– AChE inhibitors prior to testing may mask the
abnormalities and should be avoided for at least
1 day prior to testing
 Electrodiagnostic studies:
Single-fiber electromyography
• Concentric or monopolar needle
electrodes that record single
motor unit potentials
– Findings suggestive of NMF
transmission defect
– Increased jitter and normal fiber
density
– SFEMG can determine jitter
» Variability of the
interpotential interval
between two or more single
muscle fibers of the same
motor unit
 Electrodiagnostic studies:
Single-fiber electromyography
– Generalized MG
• Abnormal extensor digiti minimi found in 87%
• Examination of a second abnormal muscle will
increase sensitivity to 99%
– Occular MG
• Frontalis muscle is abnormal in almost 100%
• More sensitive than EDC (60%)
 Work-up
• Lab studies
– Interleukin-2 receptors
• Increased in generalized and bulbar forms
of MG
• Increase seems to correlate to progression
of disease
 Work-up
• Imaging studies
– Chest x-ray
• Plain anteroposterior and lateral views may identify a
thymoma as an anterior mediastinal mass
– Chest CT scan is mandatory to identify thymoma
– MRI of the brain and orbits may help to rule out
other causes of cranial nerve deficits but should
not be used routinely
 Workup
Pharmacological testing
• Edrophonium (Tensilon test)
– Patients with MG have low numbers of AChR at
the NMJ
– Ach released from the motor nerve terminal is
metabolized by Acetylcholine esterase
– Edrophonium is a short acting Acetylcholine
Esterase Inhibitor that improves muscle
weakness
– Evaluate weakness (i.e. ptosis and
opthalmoplegia) before and after administration
 Workup
Pharmacological testing

Before After
 Workup
Pharmacological testing
• Edrophonium (Tensilon test)
– Steps
• 0.1ml of a 10 mg/ml edrophonium solution is
administered as a test
• If no unwanted effects are noted (i.e. sinus
bradychardia), the remainder of the drug is injected
• Consider that Edrophonium can improve weakness in
diseases other than MG such as ALS, poliomyelitis,
and some peripheral neuropathies
 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
END..