MYASTHENIA GRAVIS transmission + normal rundown = activation of
fewer and fewer muscle fibers by successive
DESCRIPTION
 a neuromuscular disorder characterized by
weakness and fatigability of skeletal muscles
 decreased number of acetylcholine receptors
(AChRs) at neuromuscular junctions due to an
antibody-mediated autoimmune attack
PATHOPHYSIOLOGY
Normal Physiology
 At NMJ: ACh is synthesized in the motor nerve
terminal and stored in vesicles (quanta)
 Action potential travels down a motor nerve and
reaches the nerve terminal
 ACh (150 to 200 vesicles) is released -->
combines with AChRs densely packed at the
peaks of postsynaptic folds
 AChR consists of five subunits (2α, 1β, 1δ,
and 1γ or ε) arranged around a central pore
 Ach combines with α subunits of the AChR -->
channel in the AChR opens
 (+) rapid entry of cations (sodium) --> produces
depolarization at the end-plate region of the
muscle fiber
 If depolarization is large enough --> initiates
an action potential that is propagated along
the muscle fiber --> causes MUSCLE
CONTRACTION
 This process is rapidly terminated by:
 hydrolysis of Ach by acetylcholinesterase
(AChE)
 AChE: present within the synaptic folds
 diffusion of ACh away from the receptor
In Myasthenia Gravis
 Defects:
 Fundamental: decrease in the number of
available AChRs at the postsynaptic muscle
membrane
 postsynaptic folds are flattened or
“simplified”
 Result: decreased efficiency of neuromuscular
transmission
 (+) normal release of ACh BUT produces
small end-plate potentials that may fail to
trigger muscle action potentials
 Failure of transmission at many neuromuscular
junctions results in weakness of muscle
contraction
 (+) Presynaptic rundown
 Normal
 amount of ACh released per impulse
normally declines on repeated activity
 decreased efficiency of neuromuscular
nerve impulses
 Effects:
 increasing weakness or myasthenic fatigue
 accounts for the decremental response to
repetitive nerve stimulation seen on
electrodiagnostic testing
Other points to consider:
 Neuromuscular abnormalities in MG: Caused
by an autoimmune response mediated by
specific anti-AChR antibodies
 anti-AChR antibodies reduce the number
of available AChRs at neuromuscular
junctions by three distinct mechanisms:
 (1) accelerated turnover of AChRs by a
mechanism involving cross-linking and
rapid endocytosis of the receptors
 (2) damage to the postsynaptic muscle
membrane by the antibody in
collaboration with complement
 (3) blockade of the active site of the
AChR, i.e., the site that normally binds
ACh
 Anti-MuSK antibody
 occurs 40% of patients without AChR
antibody
 Immune response to muscle-specific
kinase (MuSK), a protein involved in
AChR clustering at neuromuscular
junctions --> reduction of AChRs -->
MG
 Low-density lipoprotein receptor-related
protein 4 (lrp4)
 A type of protein that is important for
clustering of AChRs in the NMJ
targeted by specific antibodies
 Found in patients whose sera are
negative or both AChR and MuSK
antibodies
 Pathogenic antibodies are IgG and are T cell
dependent
 Basis for immunotherapeutic strategies
directed against either the antibody-
producing B cells or helper T cells
 How the autoimmune response is initiated and
maintained in MG: NOT UNDERSTOOD
 BUT Thymus plays a role
 Thymus findings in MG pts:
 Hyperplastic (presence of active
germinal centers; not necessarily
enlarged)
 Thymomas (thymic tumors)
 Myoid cells
 Muscle-like cells within the thymus
  express AChRs on their surface DIAGNOSIS AND EVALUATION
 serve as a source of autoantigen
and trigger the autoimmune
reaction within the thymus gland

CLINICAL FEATURES
 Epidemiology
 Women (3:2)
 Age
 Women: 20s and 30s
 Men: 50s and 60s
 Cardinal features: weakness and fatigability of
muscles
 Weakness: increases during repeated use
(fatigue) or late in the day and may improve
following rest or sleep
 Course: Variable
 Exacerbations and remissions: occur during
the first few years after the onset of the disease
 Remissions: rarely complete or permanent
 Unrelated infections or systemic disorders:
lead to increased myasthenic weakness and
may precipitate “crisis”
 Pattern of distribution of muscle weakness
(earliest to latest):
 Diplopia and ptosis
 Facial weakness: “snarling” expression
when the patient attempts to smile
 Weakness in chewing: prolonged chewing
(meat)  Diagnosis: suspected on the basis of weakness
 Speech: nasal timbre caused by weakness and fatigability in the typical distribution without
of the palate or a dysarthric “mushy” loss of reflexes or impairment of sensation or
quality due to tongue weakness other neurologic function
 Difficulty in swallowing  Must be confirmed before treatment
 result of weakness of the palate, because of the following reasons:
tongue, or pharynx  other treatable conditions may closely
 give rise to nasal regurgitation or resemble MG
aspiration of liquids or food  treatment of MG may involve surgery
 Bulbar weakness: prominent in MuSK and the prolonged use of drugs with
antibody–positive MG potentially adverse side effects
 Generalized weakness: 85% of patients  Antibodies to AChR, MuSK, or lpr4
 Ocular MG  Virtually diagnostic of MG but a negative
 weakness that remain restricted to the result does not exclude the disease
extraocular muscles for 3 years  anti-AChR antibody: does not correspond
 Not likely to become generalized with the severity of MG BUT:
 Limb weakness: often proximal and may be  Treatment-induced fall: correlates
asymmetric with clinical improvement
 Weakness of respiration: pt is in crisis  Rise: occur with exacerbations
 DTR: preserved  Antibodies against agrin
 Agrin: protein derived from motor
nerves that normally binds to lrp4 and
may also interfere with clustering of
AChRs at neuromuscular junctions
 Electrodiagnostic testing
 Repetitive nerve stimulation
 Anti-AChE medication: stopped 6–24 h
 before testing
 best to test weak muscles or proximal
muscle groups
 Mechanism: Electric shocks are delivered
at a rate of 2-3/s to the appropriate nerves,
and action potentials are recorded from the
muscles
 Findings:
 Normal: amplitude of the evoked
muscle action potentials does not
change
 MG: rapid reduction of >10–15% in the
amplitude o the evoked responses
 Anticholinesterase test
 Drugs that inhibit the enzyme AChE allow
ACh to interact repeatedly with the limited
number of AChRs in MG, producing
improvement in muscle strength
 Edrophonium: used most commonly for
diagnostic testing d/t rapid onset (30 s) and
short duration (~5 min) of its effect
 reserved for patients with clinical findings
that are suggestive of MG but who have
negative antibody and electrodiagnostic test
results
 Procedure:
 An objective endpoint must be
selected to evaluate the effect of
edrophonium, such as:
 weakness of extraocular muscles
 impairment of speech
 length of time that the patient can
maintain the arms in forward
abduction
 initial IV dose of 2 mg of edrophonium
 Positive: (+) definite improvement -->
terminate
 No change: additional 8 mg IV
 dose is administered in two parts
because some patients react to
edrophonium with side effects such
as nausea, diarrhea, salivation,
asciculations, and rarely with
severe symptoms of syncope or
bradycardia
 Atropine (0.6 mg): drawn up in a
syringe and ready or IV
administration if these symptoms
become troublesome
 False-positive tests: occur in patients with
other neurologic disorders such as
amyotrophic lateral sclerosis, and in
placebo reactors
 Neostigmine (15 mg PO)
 longer-acting drug
 Helpful because permits more time or
detailed evaluation of strength
 Inherited/Congenital myasthenic syndromes
 Comprise a heterogeneous group of
disorders of the neuromuscular junction that
are not autoimmune but rather are due to
genetic mutations in which virtually any
component of the neuromuscular junction
may be affected
 Findings in the different forms of CMS -
Alterations in function of:
 presynaptic nerve terminal
 in the various subunits of the AChR,
AChE, or the other molecules involved
in end-plate development or
maintenance
 Similar clinical presentation with MG
 Should be suspected when:
 symptoms of myasthenia have begun in
infancy or childhood
 AChR antibody tests are consistently
negative
 Most common genetic defects occur in the
AChR or other postsynaptic molecules
 ε subunit is affected in ~75% of these
cases
 Mutations are heteroallelic
 in most of the recessively inherited
forms of CMS different mutations
affecting each of the two alleles are
present
 Differential Diagnosis
 Other conditions that cause weakness of
the cranial and/or somatic musculature
include:
 Nonautoimmune CMS
 drug-induced myasthenia
 Lambert-Eaton myasthenic syndrome
(LEMS)
 a presynaptic disorder of the
neuromuscular junction that can
cause weakness similar to that of
MG
 Most commonly affected: proximal
muscles of the lower limbs
 Distinguishing factors - LEMS have:
 depressed or absent reflexes
and experience autonomic
changes such as dry mouth
and impotence
 Nerve stimulation produces an
initial low-amplitude response
 at low rates of repetitive
stimulation (2–3Hz) -
decremental responses
like MG
 at high rates (50 Hz)
 following exercise -  mitochondrial myopathy (Kearns-Sayre
incremental responses syndrome, progressive external
occur ophthalmoplegia)
 caused by autoantibodies  Penicillamine
directed against P/Q-type  used for scleroderma or rheumatoid
calcium channels at the motor arthritis
nerve terminals --> result in  may result in true autoimmune MG, but
impaired release of ACh from the weakness is usually mild, and
nerve terminals recovery occurs within weeks or months
 Associated malignancy, most after discontinuing its use
commonly small-cell carcinoma  Aminoglycoside antibiotics or
of the lung, which may express procainamide
calcium channels that stimulate  can cause exacerbation or weakness in
the autoimmune response myasthenic patients
 Treatment:  very large doses can cause
 plasmapheresis and neuromuscular weakness in normal
immunosuppression individuals
 3,4-Diaminopyridine (3,4-DAP)
 acts by blocking K+
channels - results in
prolonged depolarization
of the motor nerve
terminals and thus
enhances ACh release
 Pyridostigmine
 prolongs the action of
ACh, allowing repeated
interactions with AChRs
 Neurasthenia
 hyperthyroidism (Graves’ disease)
 Botulism
 due to potent bacterial toxins
produced by any of eight different
strains of Clostridium botulinum
 Cause: ingestion of improperly
prepared food containing toxin
 Ubiquitous spores of C.
botulinum may germinate in
wounds
 Infants: spores may germinate
in the gastrointestinal (GI) tract
and release toxin, causing
muscle weakness
 toxins enzymatically cleave specific
proteins essential for the release of
ACh from the motor nerve terminal
--> interfering with neuromuscular
transmission
 Clinical presentation:
 myasthenia-like bulbar
weakness (e.g., diplopia,
dysarthria, dysphagia)
 lack sensory symptoms and
signs
 intracranial mass lesions
 oculopharyngeal dystrophy