2. Normal NMJ Physiology
• The NMJ essentially forms an electrical-chemical-electrical link
between nerve and muscle.
• The chemical neurotransmitter at the NMJ is acetylcholine (ACH).
• ACH molecules are packaged as vesicles in the presynaptic terminal in
discrete units known as quanta.
• each quantum contains approximately 10,000 molecules of ACH.
3. Contd....
• The quanta are in three separate stores.
• The primary, or immediately available, store consists of approximately
1000 quanta located just beneath the presynaptic nerve terminal
membrane.
• This store is immediately available for release.
4. • The secondary, or mobilization, store consists of approximately
10,000 quanta.
• Can resupply the primary store after a few seconds.
• Finally, a tertiary, or reserve, store of more than 100,000 quanta exists
far from the NMJ in the axon and cell body.
5. • When a nerve action potential invades and depolarizes the
presynaptic junction, voltage-gated calcium channels (VGCCs) are
activated, allowing an influx of calcium.
• The infusion of calcium starts a complicated interaction of many
proteins that ends in the release of ACH quanta from the presynaptic
terminal.
6. Contd....
• The greater the calcium concentration inside the presynaptic
terminal, the more quanta are released.
• ACH then diffuses across the synaptic cleft and binds to ACH
receptors (ACHRs) on the postsynaptic muscle membrane.
7. Contd....
• The postsynaptic membrane is composed of numerous junctional
folds, effectively increasing the surface area of the membrane, with
ACHRs clustered on the crests of the folds.
• The binding of ACH to ACHRs opens sodium channels, resulting in a
local depolarization, the endplate potential (EPP).
• The size of the EPP is proportional to the amount of ACH that binds to
the ACHRs.
8. • In a process similar to the generation of a nerve action potential, if
the EPP depolarizes the muscle membrane above threshold, an all-or-
none muscle fiber action potential (MFAP) is generated and
propagated through the muscle fiber.
• Under normal circumstances, the EPP always rises above the
threshold, resulting in an MFAP.
9. Contd....
• The amplitude of the EPP above the threshold value needed to
generate an MFAP is called the safety factor.
• In the synaptic cleft, ACH is broken down by the enzyme
acetylcholinesterase, and the choline subsequently is taken up into
the presynaptic terminal to be repackaged into ACH.
10. • During slow RNS (2–3 Hz) in normal subjects, ACH quanta are
progressively depleted from the primary store, and fewer quanta are
released with each successive stimulation.
• The corresponding EPP falls in amplitude, but because of the normal
safety factor, it remains above the threshold to ensure generation of
an MFAP with each stimulation.
11. • After the first few seconds, the secondary (mobilization) store begins
to replace the depleted quanta with a subsequent rise in the EPP.
• The physiology of rapid RNS (10–50 Hz) in normal subjects is more
complex.
• Depletion of quanta from the presynaptic terminal is counterbalanced
not only by the mobilization of quanta from the secondary store but
also by the accumulation of calcium.
12. • Normally, it takes about 100 ms for calcium to be actively pumped out
of the presynaptic terminal.
• If RNS is rapid enough so that new calcium influx occurs before the
previously infused calcium has been fully pumped out, calcium
accumulates in the presynaptic terminal, causing an increased release
of quanta.
13. Contd....
• Normally, this accumulation of calcium predominates over depletion,
leading to an increased number of quanta being released and a
correspondingly higher EPP.
• However, the result is the same as with any other EPP above
threshold: an all-or-none MFAP is generated.
14. • Thus, the effects of slow and rapid RNS are very different at the
molecular level, yet in normal subjects, the result is the same: the
consistent generation of an MFAP.
• In pathologic conditions where the safety factor is reduced (i.e.,
baseline EPP is reduced but still above threshold), slow RNS will cause
depletion of quanta and may drop the EPP below threshold, resulting
in the absence of an MFAP.
15. • In pathologic conditions where baseline EPP is below threshold and
an MFAP is not generated, rapid RNS may increase the number of
quanta released, resulting in a larger EPP, so that threshold is
reached.
• An MFAP is then generated where one had not been present
previously.
• These concepts form the basis of the decrements with slow RNS and
increments with rapid RNS that are seen in NMJ disorders.
16. • Neuromuscular junction disorders are a group of conditions that
cause muscle weakness.
• Their etiology can be autoimmune, congenital, metabolic, or toxic
mediated.
• The three most common neuromuscular junction disorders are
Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome
(LEMS), and botulism.
17. • The primary pathology is impaired neurotransmission at the interface
(synapse) between the nerve ending and the skeletal muscle fiber.
• In Myasthenia gravis, pathology occurs at the postsynaptic
membrane.
• In Lambert-Eaton myasthenic syndrome and botulism, the
presynaptic membrane is affected.
18. Contd....
• Neuromuscular Junction disorders patients present with complaints
of muscle fatigue and weakness that fluctuate with episodes of
worsening after activity.
• The sensory system is not affected, as sensory nerves do not have a
neuromuscular junction.
• Patients present with proximal greater than distal muscle weakness.
19. • It is common to receive complaints related to bulbar or extraocular
muscle weakness as well.
• Myasthenia gravis patients frequently present with bulbar weakness
and limb weakness.
• It is important to investigate if the patient has a history of thymoma.
20. Contd....
• LEMS patients less commonly present with bulbar weakness but have
diffuse proximal limb weakness.
• LEMS has a strong correlation with small cell carcinoma.
• Botulism is a rare condition caused by a toxin produced by clostridium
botulinum.
• In the United States majority of the cases are seen in infants.
21. Indications
• The diagnosis of the neuromuscular junction disorder derives from a
thorough history and physical examination, in addition to
electrodiagnostic studies with repetitive nerve stimulation RNS) with
exercise testing and SFEMG.
22. • SFEMG testing is the gold standard for neuromuscular junction study
with a sensitivity of up to 99%.
• Anticholinesterase medication should be stopped 8 to 24 hours
before performing the study.
23. Contraindications
• There are few absolute contraindications in performing
electrodiagnostic studies in neuromuscular junction disorder.
• Needle EMG is contraindicated in those with severe bleeding
disorders.
• Needles should also never be inserted into areas of active soft tissue
infection.
24. • NCS is contraindicated in patients with implanted cardiac
defibrillators or if connected to external defibrillators.
• Patients should have screening for pacemakers, and electrical
stimulation should not be performed directly on or near the device
itself.
25. • Routine motor and sensory nerve conduction study should first take
place to make sure no other nerve pathology exists, and the clinician
can interpret the RNS results.
• RNS involves supramaximal stimulation of a motor nerve 5-10 times
at a frequency of 3 Hz to determine compound muscle action
potential (CMAP) amplitude decrement.
26. • The 4th CMAP amplitude is compared with the first.
• A decrement of >10% is significant.
• RNS study should ideally be performed on the proximal and most
affected muscle to increase sensitivity.
27. • However, this may not be possible or easily accomplished because of
limitations in the immobilizing of the recording electrodes and the
tested muscle.
• Limb and muscle movement during the test can alter the recording
electrode leading to inaccurate results.
28. • Limb temperature should be kept warm at 32 degrees celsius.
• Colder temperature leads to increased amplitudes, prolonged
latencies, slowed conduction velocities on NCS, and decrease CMAP
decrement on RNS, leading to inaccuracy.
29. • Exercise testing is part of the RNS study routine to determine post-
exercise facilitation and exhaustion.
• If no significant decrement is observed (>10%) with baseline test, a 1-
minute exercise follows, and RNS is repeated at 1-minute intervals for
3 to 4 minutes to look for decrement due to post-exercise exhaustion.
30. • The patient is finally instructed to perform maximal isometric
contraction of the tested muscle for 10 seconds, and RNS is then
performed at a 1-minute interval for five minutes to look for
amplitude increment due to post-exercise facilitation and exhaustion.
31. • Single-fiber EMG is the most sensitive test for a patient suspected
with neuromuscular junction disorder.
• The exam is proven to be safe, however, technically challenging for
both the patient and the physician performing it.
• It requires experience and technical knowledge
32. • To perform a SFEMG, you need a contracted single fiber
electromyography needle or a facial concentric needle with a small
recording surface.
• SFEMG study looks for variations in the action potential time interval
amongst the muscle fibers from the same motor unit called a jitter.
33. • Jitter is the measurement of mean consecutive difference (MCD),
calculated between the triggered potential and the second single
muscle fiber action potential.
• Most contemporary EMG machines have software that automatically
creates the MCD calculation for you.
• The study is abnormal if the mean jitter value exceeds the upper limit
of the normal value.
34. Clinical Significance
• Motor Nerve Conduction Studies
• Since the myelin is not affected in an NMJ disorder, motor nerve
conduction velocities are normal.
• However, amplitudes may be affected, and they can assist
differentiating myasthenia gravis from LEMS.
35. • In the patient with Lambert-Eaton, CMAP decreases.
• In myasthenia gravis, CMAP is within normal limits.
36. Sensory Nerve Conduction Studies
• The neuromuscular junction is not present in sensory nerves, and
therefore the sensory nerve conduction study is normal.
37. Repetitive Nerve Stimulation/Exercise Testing
• There is no amplitude decrement between the first and the
succeeding CMAP in normal subjects.
• However, in patients with neuromuscular junction disorder, a
decrement of more than 10% between the first and the fourth
stimulation can be appreciated.
38. • In Myasthenia Gravis (MG), the baseline CMAP amplitude decrement
is observed more than 70% of the time with RNS in generalized MG.
• Not uncommonly, no decrement is appreciated on RNS of distal
muscles.
• However, a significant decrement is observable after a 1-minute
exercise.
39. • Post-exercise repair or facilitation is also observable following a brief
10-second maximum isometric contraction, followed by a decrement
in two to five minutes post-exercise due to post-exercise exhaustion.
40. • On the other hand, with Lambert-Eaton myasthenia syndrome,
baseline CMAP amplitude decrement is usually noted.
• After a brief 10-second maximum isometric muscle contraction, post-
exercise facilitation of up to 200% increase in CMAP amplitude is
typical.
• In two to five minutes, the clinician should note post-exercise
exhaustion.
41. • Other neurologic disorders that can also show CMAP decrement on
RNS include
motor neuron disease, conditions where on-going denervation and
reinnervation result in immature nerve endings/neuromuscular
junction, and
myopathies
42. Single Fiber EMG
• Single-fiber EMG reveals increased jitter and blocking in
neuromuscular junction disorder.
• There is marked prolongation in jitter value, with MCD of more than
100 microseconds.
• It is highly sensitive in the diagnosis of NMJ disorder but is not
specific to myasthenia gravis.
43. • Pathologic conditions that involve reinnervation and hence immature
nerve endings will also show increased jitter.
• Due to the high sensitivity of the test, neuromuscular junction
disorder can be ruled out with a normal SFEMG study of a weak
muscle.
44. Late Responses
• H-reflexes and F-reflex are not routinely part of the process in a
neuromuscular junction study as it does not provide additional useful
information.
45. Needle EMG
• For a neuromuscular junction study, all muscles that are weak in the
patient should be examined in the needle EMG portion of the test.
• During the exam, the diagnostician may notice unstable MUAPs with
normal recruitment.
• Most Neuromuscular junction disorders will not show abnormal
spontaneous activity except for in botulism.
46. • CMAP decrement on RNS in patients with findings of muscle
denervation or myotonic discharge on needle EMG study does not
signify NMJ disorder.
47.
48. • Acquired myasthenia gravis (MG) is a disorder of neuromuscular
transmission, resulting from binding of autoantibodies to components
of the neuromuscular junction, most commonly the acetylcholine
receptor (AChR).
• The incidence ranges from 0.3 to 2.8 per 100,000,1 and it is estimated
to affect more than 700,000 people worldwide.
49. • The increasing use of immunomodulating therapies has been a major
factor in improving the prognosis for patients with MG in recent
years.
• The various treatment options must be weighed in the context of
individual patient factors.
50. Why do we need MG guidance treatment
statements?
• Although there is widespread agreement on the use of many
treatments for MG, there is no internationally accepted standard of
care.
• Because MG is heterogeneous, no one treatment approach is best for
all patients.
• Few physicians treat enough patients with MG to be comfortable with
all available treatments.
51. • Given its heterogeneity, the few randomized controlled trials (RCTs) in
MG have limited generalizability, while uncontrolled trials are limited
by potential bias.
• Hence, an effort to develop consensus among international experts
was undertaken to guide clinicians worldwide on the multifaceted
approach to managing MG
52. • Guidance statements were developed for the following:
Symptomatic and immunosuppressive (IS) treatments
IV immunoglobulin (IVIg) and plasma exchange (PLEX)
Impending and manifest myasthenic crisis
54. Definition of remission
• The patient has no symptoms or signs of MG.
• Weakness of eyelid closure is accepted, but there is no weakness of
any other muscle on careful examination.
• Patients taking cholinesterase inhibitors (ChEIs) every day with
reasonable evidence to support symptomatic benefit are therefore
excluded from this category.
55. • 3. Definition of ocular MG (based on dysfunction due to MG at a
specified point in time, and not dependent upon the duration of
disease).
• MGFA Class I3: Any ocular muscle weakness.
• May have weakness of eye closure.
56. • Strength in all other facial, bulbar, and limb muscles is normal.
• (It is recognized that some patients report fatigue when strength
testing is normal.
• The physician should use clinical judgment in attributing fatigue to
generalized MG in the absence of objective nonocular weakness).
57. • 4. Definition of impending myasthenic crisis.
• Rapid clinical worsening of MG that, in the opinion of the treating
physician, could lead to crisis in the short term (days to weeks).
58. • 5. Definition of manifest myasthenic crisis (the concept of crisis
focuses on the clinical implications—it represents a serious, life-
threatening, rapid worsening of MG and potential airway compromise
from ventilatory or bulbar dysfunction).
59. • MGFA Class V3: Worsening of myasthenic weakness requiring
intubation or noninvasive ventilation to avoid intubation, except
when these measures are employed during routine postoperative
management (the use of a feeding tube without intubation places the
patient in MGFA Class IVB3).
60. • 6. Definition of refractory MG.
• PIS3 is unchanged or worse after corticosteroids and at least 2 other
IS agents, used in adequate doses for an adequate duration, with
persistent symptoms or side effects that limit functioning, as defined
by patient and physician.
• Consensus guidance treatment statements.
61. Symptomatic and IS treatment of MG.
• 1. Pyridostigmine should be part of the initial treatment in most
patients with MG.
• Pyridostigmine dose should be adjusted as needed based on
symptoms.
62. • The ability to discontinue pyridostigmine can be an indicator that the
patient has met treatment goals and may guide the tapering of other
therapies.
• Corticosteroids or IS therapy should be used in all patients with MG
who have not met treatment goals after an adequate trial of
pyridostigmine.
63. • 2. A nonsteroidal IS agent should be used alone when corticosteroids
are contraindicated or refused.
• A nonsteroidal IS agent should be used initially in conjunction with
corticosteroids when the risk of steroid side effects is high based on
medical comorbidities.
64. • A nonsteroidal IS agent should be added to corticosteroids when:
Steroid side effects, deemed significant by the patient or the treating
physician, develop
Response to an adequate trial (table e-1) of corticosteroids is
inadequate; or
The corticosteroid dose cannot be reduced due to symptom relapse.
65. • 3. Nonsteroidal IS agents that can be used in MG include
azathioprine, cyclosporine, mycophenolate mofetil, methotrexate,
and tacrolimus.
• The following factors should be considered in selecting among these
agents:
• a. There is widespread variation in practice with respect to choice of
IS agent since there is little literature comparing them.
66. • b. Expert consensus and some RCT evidence support the use of azathioprine
as a first-line IS agent in MG.
• c. Evidence from RCTs supports the use of cyclosporine in MG, but potential
serious adverse effects and drug interactions limit its use.
• d. Although available RCT evidence does not support the use of
mycophenolate and tacrolimus in MG, both are widely used, and one or both
are recommended in several national MG treatment guidelines.
67. • 4. Patients with refractory MG should be referred to a physician or a
center with expertise in management of MG.
68. • In addition to the previously mentioned IS agents, the following
therapies may also be used in refractory MG:
• a. Chronic IVIg and chronic PLEX
• b. Cyclophosphamide;
• c. Rituximab, for which evidence of efficacy is building, but for which
formal consensus could not be reached.
69. • 5. IS agent dosage and duration of treatment
• a. Once patients achieve treatment goals, the corticosteroid dose
should be gradually tapered.
• In many patients, continuing a low dose of corticosteroids long-term
can help to maintain the treatment goal.
70. • b. For nonsteroidal IS agents, once treatment goals have been
achieved and maintained for 6 months to 2 years, the IS dose should
be tapered slowly to the minimal effective amount.
• Dosage adjustments should be made no more frequently than every
3–6 months.
71. • c. Tapering of IS drugs is associated with risk of relapse, which may
necessitate upward adjustments in dose.
• The risk of relapse is higher in patients who are symptomatic, or after
rapid taper.
72. • d. It is usually necessary to maintain some immunosuppression for
many years, sometimes for life.
• 6. Patients must be monitored for potential adverse effects and
complications from IS drugs.
• Changing to an alternative IS agent should be considered if adverse
effects and complications are medically significant or create undue
hardship for the patient.
73. IVIg and PLEX
• 1. PLEX and IVIg are appropriately used as short-term treatments in patients with MG with life-
threatening signs such as
respiratory insufficiency or dysphagia;
in preparation for surgery in patients with significant bulbar dysfunction;
when a rapid response to treatment is needed;
when other treatments are insufficiently effective; and
prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations
74. • 2. The choice between PLEX and IVIg depends on individual patient
factors (e.g., PLEX cannot be used in patients with sepsis and IVIg
cannot be used in renal failure) and on the availability of each.
75. • 3. IVIg and PLEX are probably equally effective in the treatment of severe
generalized MG.
• 4. The efficacy of IVIg is less certain in milder MG or in ocular MG.
• 5. PLEX may be more effective than IVIg in MuSK-MG.
• 6. The use of IVIg as maintenance therapy can be considered for patients with
refractory MG or for those in whom IS agents are relatively contraindicated.
76. • Impending and manifest myasthenic crisis.
• Impending and manifest myasthenic crisis are emergent situations requiring
aggressive management and supportive care.
• Although cholinergic crises are now rare, excessive ChEI cannot be completely
excluded as a cause of clinical worsening.
• Also, ChEIs increase airway secretions, which may exacerbate breathing
difficulties.
77. • PLEX and IVIg are the mainstay of management in myasthenic crisis.
• 1. Impending crisis requires hospital admission and close observation
of respiratory and bulbar function, with the ability to transfer to an
intensive care unit if it progresses to manifest crisis.
• Myasthenic crisis requires admission to an intensive care or step-
down unit to monitor for or manage respiratory failure and bulbar
dysfunction.
78. • 2. PLEX and IVIg are used as short-term treatment for impending and
manifest myasthenic crisis and in patients with significant respiratory or
bulbar dysfunction.
• Corticosteroids or other IS agents are often started at the same time to
achieve a sustained clinical response.
• (Because corticosteroids may cause transient worsening of myasthenic
weakness, it may be appropriate to wait several days for PLEX or IVIg to have a
beneficial effect before starting corticosteroids).
79. • 3. Although clinical trials suggest that IVIg and PLEX are equally effective in the
treatment of impending or manifest myasthenic crisis, expert consensus
suggests that PLEX is more effective and works more quickly.
• The choice between the 2 therapies depends on patient comorbidity (e.g.,
PLEX cannot be used in sepsis and IVIg is contraindicated in hypercoagulable
states, renal failure, or hypersensitivity to immunoglobulin) and other factors,
including availability.
80. • A greater risk of hemodynamic and venous access complications with
PLEX should also be considered in the decision (many complications
of PLEX are related to route of access and may be minimized by using
peripheral rather than central venous access).
81. Thymectomy in MG
• 1. In non-thymomatous MG, thymectomy is performed as an option
to potentially avoid or minimize the dose or duration of
immunotherapy, or if patients fail to respond to an initial trial of
immunotherapy or have intolerable side-effects from that therapy.
82. • Because of the long delay in onset of effect, thymectomy for MG is an
elective procedure.
• It should be performed when the patient is stable and deemed safe to
undergo a procedure where postoperative pain and mechanical
factors can limit respiratory function.
83. • 2. The value of thymectomy in the treatment of prepubertal patients
with MG is unclear, but thymectomy should be considered in children
with generalized AChR antibody–positive MG:
• a. If the response to pyridostigmine and IS therapy is unsatisfactory;
or
• b. In order to avoid potential complications of IS therapy.
84. • For children diagnosed with seronegative generalized MG, the
possibility of a congenital myasthenic syndrome or other
neuromuscular condition should be entertained, and evaluation at a
center specializing in neuromuscular diseases is of value prior to
thymectomy.
85. • 3. With rare exceptions, all patients with MG with thymoma should
undergo surgery to remove the tumor.
• Removal of the thymoma is performed to rid the patient of the tumor
and may not produce improvement in MG.
• All thymus tissue should be removed along with the tumor.
86. • Further treatment of thymoma will be dictated by histologic
classification and degree of surgical excision.
• Incompletely resected thymomas should be managed after surgery
with an interdisciplinary treatment approach (radiotherapy,
chemotherapy).
87. • 4. In elderly or multimorbid patients with thymoma, palliative
radiation therapy can be considered in the appropriate clinical setting.
• Small thymomas may be followed without treatment unless they are
enlarging or become symptomatic.
88. • 5. Endoscopic and robotic approaches to thymectomy are increasingly
performed and have a good track record for safety in experienced centers.
• Data from randomized, controlled comparison studies are not available.
• Based on comparisons across studies, less invasive thymectomy approaches
appear to yield similar results to more aggressive approaches.
89. • 6. Thymectomy may be considered in patients with generalized MG
without detectable AChR antibodies if they fail to respond adequately
to IS therapy, or to avoid/minimize intolerable adverse effects from IS
therapy.
• Current evidence does not support an indication for thymectomy in
patients with MuSK, LRP4, or agrin antibodies.
90. Juvenile MG
• 1. Children with acquired autoimmune ocular MG are more likely
than adults to go into spontaneous remission.
• Thus, young children with only ocular symptoms of MG can be
treated initially with pyridostigmine.
• Immunotherapy can be initiated if goals of therapy are not met.
91. • 2. Children are at particular risk of steroid side effects, including
growth failure, poor bone mineralization, and susceptibility to
infection, due in part to a delay in live vaccinations.
• Long-term treatment with corticosteroids should use the lowest
effective dose to minimize side effects.
• 3. Maintenance PLEX or IVIg are alternatives to IS drugs in JMG.
92. MG with MuSK antibodies
• 1. Many patients with MuSK-MG respond poorly to ChEIs, and
conventional pyridostigmine doses frequently induce side effects.
• 2. Patients with MuSK-MG appear to respond well to corticosteroids
and to many steroid-sparing IS agents.
• They tend to remain dependent on prednisone despite concomitant
treatment with steroid-sparing agents.
93. • 3. MuSK-MG responds well to PLEX, while IVIg seems to be less
effective.
• 4. Rituximab should be considered as an early therapeutic option in
patients with MuSK-MG who have an unsatisfactory response to
initial immunotherapy.
94. MG in pregnancy
• 1. Planning for pregnancy should be instituted well in advance to
allow time for optimization of myasthenic clinical status and to
minimize risks to the fetus.
• 2. Multidisciplinary communication among relevant specialists should
occur throughout pregnancy, during delivery, and in the postpartum
period.
95. Contd....
• 3. Provided that their myasthenia is under good control before
pregnancy, the majority of women can be reassured that they will
remain stable throughout pregnancy.
• If worsening occurs, it may be more likely during the first few months
after delivery.
96. Contd....
• 4. Oral pyridostigmine is the first-line treatment during pregnancy.
• IV ChEIs may produce uterine contractions and should not be used
during pregnancy.
• 5. Thymectomy should be postponed until after pregnancy as benefit
is unlikely to occur during pregnancy.
97. Contd....
• 6. Chest CT without contrast can be performed safely during
pregnancy, although the risks of radiation to the fetus need to be
carefully considered.
• Unless there is a compelling indication, postponement of diagnostic
CT until after delivery is preferable.
98. Contd....
• 7. Prednisone is the IS agent of choice during pregnancy.
• 8. Current information indicates that azathioprine and cyclosporine
are relatively safe in expectant mothers who are not satisfactorily
controlled with or cannot tolerate corticosteroids.
99. Contd....
• Current evidence indicates that mycophenolate mofetil and
methotrexate increase the risk of teratogenicity and are
contraindicated during pregnancy.
• (These agents previously carried Food and Drug Administration [FDA]
Category C (cyclosporine), D (azathioprine and mycophenolate
mofetil), and X (methotrexate) ratings.
100. Contd....
• The FDA has recently discontinued this rating system, and replaced it
with a summary of the risks of using a drug during pregnancy and
breastfeeding, along with supporting data and “relevant information
to help health care providers make prescribing and counseling
decisions”12).
101. Contd....
• Although this statement achieved consensus, there was a strong
minority opinion against the use of azathioprine in pregnancy.
• Azathioprine is the nonsteroidal IS of choice for MG in pregnancy in
Europe but is considered high risk in the United States.
• This difference is based on a small number of animal studies and case
reports.
102. Contd....
• 9. PLEX or IVIg are useful when a prompt, although temporary,
response is required during pregnancy.
• Careful consideration of both maternal and fetal issues, weighing the
risks of these treatments against the requirement for use during
pregnancy and their potential benefits, is required.
• 10. Spontaneous vaginal delivery should be the objective and is
actively encouraged.
103. • 11. Magnesium sulfate is not recommended for management of
eclampsia in MG because of its neuromuscular blocking effects;
barbiturates or phenytoin usually provide adequate treatment.
• 12. All babies born to myasthenic mothers should be examined for
evidence of transient myasthenic weakness, even if the mother's
myasthenia is well-controlled, and should have rapid access to
neonatal critical care support.
104. Differential Diagnosis
• The differential diagnosis for myasthenia gravis include the following:
• Lambert-Eaton syndrome
• fluctuating weakness that improves with exercise, differentiating it from
MG.
• This is usually due to underlying malignancy, most commonly small-cell
lung cancer.
• It affects voltage-gated calcium channels in the presynaptic membrane.
105. Contd....
• Cavernous sinus thrombosis
• Can present with persistent ocular findings, photophobia, chemosis,
and headaches.
• It is usually abrupt in onset but can be fulminant, and causes can be
septic or aseptic.
106. Contd....
• Brainstem gliomas
• malignant tumors that present with bulbar symptoms, weakness,
numbness, balance problems, and seizures depending on its location
and structures affected.
• The symptoms are persistent and usually present with headaches and
signs of increased intracranial pressure.
107. Contd....
• Multiple sclerosis
• can present with any neurological sign that may fluctuate or persist over hours
to days to weeks secondary to demyelination in the central nervous system.
• This may present with weakness, sensory deficits, cognitive and behavioral
issues.
• Weakness may be unilateral or bilateral and is usually accompanied by upper
motor neuron signs like hyperreflexia, spasticity, and a positive Babinski.
108. Contd....
• Botulism
• presents with ptosis, double vision, progressive weakness, and
pupillary abnormalities accompanied by systemic symptoms.
• Ingestion of honey or contaminated foods may be elicited in the
patient's history.
109. Contd....
• Tick-borne disease
• presents with ascending paralysis and respiratory distress and
decreased reflexes from a neurotoxin from the saliva of ticks.
• Minimal constitutional symptoms are seen.
• It can sometimes present with ophthalmoplegia and bulbar
symptoms.
110. Contd....
• Polymyositis and dermatomyositis
• cause proximal muscle weakness and is usually associated with pain.
• The pathology is the inflammation of the muscle itself.
• Graves ophthalmopathy
• presents with eyelid retraction and widened palpebral fissure.
• These are caused by autoantibodies targeted toward the structures of the eye.
111. Cramps, Pains, Fatigue and Exertional Symptoms
• Cramps and muscle pains are common.
• Cramp refers to a painful knotting up of muscles, usually affecting calf
muscles.
• These are seen in endocrine diseases like hypothyroidism, electrolyte
disturbances, renal diseases and metabolic myopathies like McArdle
disease.
112. • In a large proportion of patients, the precise mechanism cannot be
deciphered.
• Diffuse aches and pains are also very common and are known to be
the presenting symptom of osteomalacic myopathies.
113. • These are also associated with rheumatological conditions like
polymyalgia rheumatica.
• When these symptoms are not associated with weakness, the
diagnostic yield is less.
114. • Fatigue is more often a manifestation of systemic diseases like
anaemia and hepatic or renal dysfunctions.
• Most individuals refer to fatigue in a general way, meaning thereby
difficulty and tiredness in performing activities.
115. Contd....
• Fatigability of neuromuscular disorders is distinct, as it tends to
• involve selected groups of muscles like eyelids, external ocular
movements, chewing, swallowing, neck extension, etc. and
• exhibit diurnal fluctuation with intermittent normalcy
116. Contd....
• The difference between weakness and fatigue is the first contraction,
which is strong in the latter.
• Exercise-related exacerbations of symptoms are common with
metabolic myopathies, storage diseases and periodic paralysis,
• but it is important to remember that almost all sufferers of weakness
will experience some increase of difficulty and sense of fatigue when
exercising affected muscles.
117. • AChR antibodies are predominantly of the IgG1 and IgG3 subclasses.
• IgG2 and IgG4 subclasses are also identified, but in fewer cases.
• The pathogenic mechanisms and functional spectrum of AChR
antibodies are varied, but overall, they impair receptor function by
either binding, blocking, or modulating its activity.
118. Contd....
• The predominant mechanism is the binding of the antibody and
activation of the complement cascade →leading to the formation of
the membrane attack complex→causes damage of the postsynaptic
membrane and destruction of synaptic folds which contain AChRs and
associated proteins, including voltage-gated sodium channels.
119. Contd....
• Other mechanisms of pathogenicity include:
antigenic modulation by the binding and crosslinking of AChRs, leading to
increased endocytosis and degradation [37]; and
the impairment of AChR function, either by the blocking of ACh binding to the
receptor or the prevention of channel opening.
• Most blocking antibodies appear in association with binding antibodies, and
only rarely are they unique.
120. Clinical Manifestations
• The core clinical manifestation of MG is fatigable muscle weakness,
worsened by exertion and improved by rest.
• The most common presenting symptoms are ocular, with double
vision and ptosis.
121. Contd....
• Most patients will develop diplopia and/or ptosis some time during
the course of their disease.
• In addition, up to 80% of patients with ocular onset will go on to
develop generalized symptoms, usually within two years of disease
onset.
122. Contd....
• Bulbar muscles are also frequently involved, resulting in
flaccid dysarthria
dysphagia, and
facial and jaw weakness
123. Contd....
• Axial weakness
with neck flexion weakness usually more common than weakness of
neck extension.
• Head-drop was associated with age >60 and male patients in that
study.
124. Contd....
• Limb muscle weakness tends to be symmetric and proximal, and
patients commonly complain of difficulty climbing stairs, getting up
from chairs, and raising arms above their head.
125. Contd....
• In some instances, distal muscles can be predominantly affected,
either in a symmetric or asymmetric distribution.
• For example, some patients complain of weakness in finger and wrist
extension and flexion, as well as foot drop.
126. Contd....
• Finally, 15–20% of patients with AChR-MG can develop respiratory
weakness requiring mechanical ventilation (MG crisis).
• Spontaneous remissions for different lengths of time may occur in the
course of adult-onset MG.
127. • In an earlier study conducted before the widespread use of steroids
and other immunosuppressants, approximately one fourth of the
patients had a complete or near complete spontaneous remission,
lasting an average of 4.6 years and up to 17 years.
128. • Half of the remissions occurred during the first year after onset.
• A study of Oosterhuis et al. found that 22% of patients treated with
anticholinesterase medications only had spontaneous remission [42].
• The remission lasted more than 12 months in duration in half of those
patients, with the maximum duration of the remission being 6 years
in that study.
129. • The role of AChE in the hydrolyzation of ACh is therefore crucial, as it prevents
a single molecule of ACh from repetitively activating AChRs.
• The effectiveness of neuromuscular junction transmission is also determined
by
the amount of ACh released by the nerve terminal
the density of ACh receptors in the postsynaptic membrane, and
the density of voltage-gated sodium channels at the endplate.
130. • The latter is dependent on the presence of folds in the postsynaptic
membrane.
• These folds determine the density of the voltage-gated sodium
channels in the postsynaptic membrane, and therefore increase the
efficient coupling of the localized EPP to the myofiber action potential
131. • Neuromuscular junction disorders such as MG disrupt the cascade of
events that lead to reliable muscle contraction.
• In addition, there is a reduction in the number of AChRs and voltage-
gated sodium channels as the result of complement-related injury to
the postsynaptic membrane in MG.
132. • The resultant inefficient neuromuscular transmission is reflected in
decremental response in the amplitude of compound muscle action
potential (CMAP) during repetitive nerve stimulation (RNS) and
abnormal jitter or blocking in single fiber EMG.
133. Autoimmune Antibodies
• The NMJ is susceptible to autoimmune pathology because there is no
blood-nerve barrier to protect the NMJ.
• The precise mechanisms triggering autoimmunity at the NMJ are
unknown, but the thymus is known to play a role.
• Extensive research has shown the complex autoimmune nature of
MG.
134. • Antibodies against the AChR are found in approximately 80% of
patients with MG and are of the immunoglobulin (Ig) G1 or IgG3
subclass.
• False-positive AChR antibodies are extremely rare (<1%) and often are
seen in related disorders LEMS] or motor neuron disease.
135. • A majority of these are AChR-“binding” antibodies.
• AChR-“modulating” antibodies are found in less than 1% of MG
patients without binding antibodies, and
• “Blocking” antibodies are found in approximately 10% of MG patients
without binding antibodies.
136. • The polyclonal IgG antibodies to AChR are produced by plasma cells in
peripheral lymphoid organs, bone marrow, and thymus.
• These cells are derived from B cells that have been activated by
antigen-specific T-helper (CD41) cells.
137. • The T cells have also been activated, in this case, by binding to AChR
antigenic peptide sequences (epitopes) that rest on the
histocompatibility antigens on the surface of antigen-presenting cells.
• Most common are anti-AChR binding antibodies, which bind to the
AChR on the postsynaptic membrane and cause the complement-
mediated destruction of the junctional folds and accelerate
internalization and degradation of AChR.
138. • Blocking antibodies prevent ACh binding to the AChR.
• Modulating antibodies distort the NMJ and folds.
• The end result in all cases is a loss of functional AChR.
• The AChR antibodies react with multiple determinants, and enough
antibodies circulate to saturate up to 80% of all AChR sites on muscle.
139. Contd....
• A small percentage of the anti-AChR molecules interfere directly with the
binding of ACh.
• the major damage to endplates seems to result from actual loss of receptors
owing to complement-mediated lysis of the membrane and to acceleration of
normal degradative processes (internalization, endocytosis, lysosomal
hydrolysis) with inadequate replacement by new synthesis.
140. • As a consequence of the loss of AChR and the erosion and
simplification of the endplates, the amplitude of miniature endplate
potentials is about 20% of normal, and patients are abnormally
sensitive to the competitive antagonist curare.
141. • The characteristic decremental response to repetitive stimulation of
the motor nerve reflects failure of endplate potentials to reach
threshold so that progressively fewer fibers respond to arrival of a
nerve impulse.
142. • Most AChR antibodies are directed against antigenic determinants on
the extracellular portion of the protein farthest out from the
membrane rather than the ACh-binding site.
• The summed effects of the polyclonal anti-AChR antibodies, especially
those that fix complement, result in destruction of the receptors.
143. • Physiologic studies indicate impaired postsynaptic responsiveness to
ACh, which accounts for the physiologic abnormalities, clinical
symptoms, and beneficial effects of drugs that inhibit
acetylcholinesterase.
