Myasthenia gravis

• MG is an autoimmune disorder of the postsynaptic
neuromuscular junction characterized by fluctuating
weakness involving variable combinations of ocular,
bulbar, limb, and respiratory muscles.
• Once uniformly disabling and sometimes fatal, MG can
be managed effectively with therapies that include
anticholinesterase agents, rapid immunomodulatory
therapies, chronic immunosuppressive agents, and
thymectomy.
• Treatment is individualized and depends upon the age
of the patient; the severity of the disease, particularly
dictated by respiratory or bulbar involvement; and the
pace of progression

• There are two clinical forms of myasthenia
gravis: ocular and generalized.
●In ocular myasthenia, the weakness is limited
to the eyelids and extraocular muscles.
●In generalized disease, the weakness
commonly affects ocular muscles, but it also
involves a variable combination of bulbar,
limb, and respiratory muscles.

• Patients who have detectable antibodies to the
acetylcholine receptor (AChR), muscle-specific receptor
tyrosine kinase (MuSK), or lipoprotein receptor-related
protein 4 (LRP4) are considered to have seropositive
myasthenia gravis,
• while those lacking these antibodies on standard assays are
considered to have seronegative myasthenia.
• Approximately 50% patients with purely ocular myasthenia
are seropositive, compared with approximately 90 % of
those with generalized disease.
• Another important consideration is that approximately 10
to 15 % of patients with myasthenia gravis have an
underlying thymoma.

At the postsynaptic membrane, muscle-specific tyrosine kinase (MuSK) is
associated with the low-density lipoprotein receptor-related protein 4 (Lrp4).
MuSK activation through agrin-Lrp4 binding triggers a signaling pathway, which
includes Dok7 recruitment, leading to AChR clustering. Acetylcholinesterase (AChE)
binds through its collagen Q (ColQ) tail to perlecan and MuSK.

• Myasthenia gravis occurs at any age, but there
tends to be a bimodal distribution to the age
of onset, with an early peak in the 20-30 years
(female predominance) and a late peak in the
60-80 years (male predominance).
• A population-based case-control study found
that women in the postpartum period had an
increased risk for the clinical onset of
myasthenia gravis.

• Autoimmune juvenile myasthenia gravis accounts for
approximately 10 to 15 % of cases in North America.
• In neonates, a transient form of myasthenia, called
neonatal myasthenia gravis, can occur as a result of the
transplacental passage of maternal antibodies that
interfere with function of the neuromuscular junction.
• Rare, nonimmune-mediated forms, collectively
referred to as congenital myasthenia gravis, may be the
result of mutations that adversely affect
neuromuscular transmission.

NEONATAL MYASTHENIA GRAVIS
• Transient neonatal myasthenia gravis occurs in 10 to 20 % of infants born to
mothers with myasthenia gravis.
• Most mothers of affected infants have active clinical disease, although some
may have no evidence of myasthenia or may be in remission.
• Maternal AChR antibodies transferred to the fetus are responsible for transient
neonatal myasthenia gravis.
• Higher ratios of antibodies directed against the fetal versus the adult type of
AChR in mothers with myasthenia gravis are correlated with an increased
likelihood of transmitting the disorder.
• Rarely, there are persistent myopathic sequelae related to the fetal
acetylcholine receptor inactivation syndrome (FARIS). Although the
pathophysiologic mechanism is not established, this condition is probably
related to elevated levels of maternal AChR antibodies directed against the
fetal subunit of the AChR receptor, causing abnormal endplate development of
the embryonic neuromuscular junction in a subset of infants. The facial and
bulbar musculature may be particularly susceptible to permanent injury
caused by this process.
• Among mothers with a child affected by transient neonatal MG, the risk of
recurrence with subsequent pregnancies is approximately 75 %.

Clinical features
• Neonatal myasthenia gravis typically presents within a few hours of birth. Signs
are always apparent by the third day of age.
• More severely affected infants have a history of polyhydramnios and may have
arthrogryposis multiplex (multiple joint contractures) at birth.
• Newborns with myasthenia have generalized weakness and hypotonia.
However, deep tendon reflexes are present.
• Facial diplegia often occurs; ptosis and ophthalmoplegia occur less often.
• Bulbar weakness is frequent, leading to poor sucking and swallowing and a
weak cry. Pooling of secretions and respiratory muscle weakness may
contribute to respiratory failure and the need for assisted ventilation.
• With prompt diagnosis and appropriate management, most newborns recover
within a few weeks.
• Treatment is more difficult and recovery is slower in more severely affected
patients.
• In the rare fetal acetylcholine receptor inactivation syndrome, there are
persistent manifestations characterized by facial and bulbar myopathy or
arthrogryposis multiplex congenita, sometimes accompanied by hearing loss or
pyloric stenosis

Diagnosis
• The diagnosis of neonatal myasthenia gravis should be suspected in
the infant of a mother with myasthenia.
• If the mother does not have known disease, the diagnostic test is the
response of the infant to administration of an acetylcholinesterase
inhibitor.
• The agent used most commonly is neostigmine methylsulfate (0.15
mg/kg IM or SQ).
• When the test is diagnostic, neostigmine results in clinical
improvement that begins in approximately 15 minutes and continues
for one to three hours.
• Success should be determined by a measurable response (eg, an
improvement in ventilation or time to drink an amount of fluid) of
>15 %.
• Atropine may be needed to control muscarinic side effects, such as
diarrhea and increased tracheal secretions.

• Some experts prefer the acetylcholinesterase
inhibitor edrophonium (0.15 mg/kg IM or SQ, or IV in fractional
amounts delivered over several minutes after a test dose of 0.03
mg/kg), but it is no longer available in the US, Canada, the UK,
European Union, or many other countries.
• This agent acts more rapidly than neostigmine, and muscarinic side
effects are less intense.
• However, respiratory arrest occasionally occurs.
• Complications of prematurity or hypoxic-ischemic encephalopathy may
occasionally interfere with an infant's response to administration of an
acetylcholinesterase inhibitor.
• In these cases, RNS can be used to confirm the diagnosis. This test
compares the amplitude of the fifth evoked compound muscle action
potential with the first, before and after administration of an
acetylcholinesterase inhibiting agent.
• A positive response is reduction of the fifth action potential by 10 % or
more and reversal of this decrement by the acetylcholinesterase
inhibitor

MANAGEMENT
• Management of neonatal myasthenia is supportive.
• Small frequent feedings are provided by nasogastric or orogastric
tube, and assisted ventilation is provided if needed.
• In addition, neostigmine methylsulfate (0.05 to 0.1 mg/kg IM or SQ)
is given 30 minutes before each feeding.
• When feeding and respiratory abnormalities have improved, the
drug can be given orally (0.5 to 1.0 mg/kg PO approximately 45
minutes prior to feeding). Excessive doses may result in increased
secretions, diarrhea, weakness, and muscle fasciculations.
• With continued clinical improvement, the neostigmine dose can be
lowered gradually. In addition, the course of the disease can be
monitored by repeat nerve stimulation testing and measurement of
acetylcholine receptor antibodies.

• In one case of a child (age five years) with
severe facial muscle weakness due to
suspected fetal acetylcholine receptor
inactivation syndrome, prior treatment
with pyridostigmine was not beneficial, but
there was significant symptom improvement
with albuterol.

PROGNOSIS
• With prompt diagnosis and appropriate management, most
newborns recover within a few weeks;
• 90% of patients recover fully before reaching two months
of age.
• Tube feeding and assisted ventilation rarely are required for
longer than one to two weeks.
• The average duration of pharmacologic treatment is four
weeks.
• The fetal acetylcholine receptor inactivation syndrome has
been associated with a broad spectrum of severity, ranging
from profound arthrogryposis, respiratory weakness, and
early death to mild but permanent weakness of the facial
and bulbar muscles

CONGENITAL MYASTHENIC
SYNDROMES
• Congenital myasthenic syndromes (CMS) are
uncommon causes of neuromuscular junction
failure in newborns.
• These heterogeneous disorders are caused by
genetic defects in presynaptic, synaptic basal
lamina, and postsynaptic components of the
neuromuscular junction.
• There is no involvement of the immune
system

The more common types of CMS
●Primary acetylcholine receptor (AChR) deficiency, the most
frequent type, caused by recessive mutations in any of the
AChR subunit genes (CHRNA, CHRNB, CHRND, or CHRNE);
most occur in the epsilon subunit (CHRNE)
●RAPSN mutations, causing impaired clustering of AChR
●COLQ mutations, leading to endplate acetylcholinesterase
deficiency
●DOK7 mutations, resulting in aberrant synaptic maturation
and maintenance
●Fast channel syndrome with abbreviated AChR channel
opening, caused by mutations in the AChR subunit genes
(CHRNA, CHRNB, CHRND, or CHRNE)
●Slow channel syndrome with prolonged AChR channel
opening, also caused by mutations in the AChR subunit
genes (CHRNA, CHRNB, CHRND, or CHRNE)

Clinical features
• All forms of CMS are characterized by fatigable
weakness, but some forms have distinct
phenotypes.
• Newborns with CMS frequently have ptosis, in
contrast to patients with transient neonatal
myasthenia gravis.
• In addition, several subtypes of CMS (eg, primary
acetylcholine receptor deficiency,
acetylcholinesterase deficiency, and fast channel
syndrome) typically demonstrate ophthalmoplegia.

• Bulbar and respiratory muscle weakness are
common features in these subtypes. Affected
infants may have fluctuating generalized
hypotonia and weakness and life-threatening
episodes of apnea.
• Arthrogryposis may be present at birth.
• Congenital myasthenia often improves with age,
but spontaneous exacerbations may occur and
sometimes result in sudden death in infancy.
• Increased or intense activity, febrile illness, or
stress may induce exacerbations.

Diagnosis
• The diagnosis of CMS should be suspected in the setting of fatigable
weakness affecting mainly the ocular and bulbar muscles, onset at birth to
early childhood, and a positive family history.
• Nonetheless, some types of CMS present later in life, and some present
with a limb-girdle distribution of weakness with little or no involvement of
the cranial muscles.
• A diagnostic response to acetylcholinesterase inhibitors may be useful if it
is positive.
• However, some disorders, such as DOK7, slow channel syndrome, and
COLQ, may be refractory to these agents or worsened by administration.
• A decremental response to repetitive nerve stimulation at low frequency
(2 Hz) supports the diagnosis, though infants with choline
acetyltransferase CMS due to CHAT mutations require prolonged
stimulation at a higher frequency (10 Hz) to induce a response.
• Targeted genetic testing can be diagnostic when phenotypic
characteristics suggest specific genetic mutations that cause CMS .
• Next generation whole-exome sequencing can identify causative genetic
mutations when targeted genetic testing is not feasible or is
nondiagnostic. A definitive genetic diagnosis is useful for guiding
treatment, prognosis, and genetic counseling

Management
• The treatment of CMS depends upon the specific disorder.
• A trial of acetylcholinesterase inhibitor treatment
(eg, pyridostigmine) is warranted for some but not all types of
CMS; certain disorders (eg, DOK7, slow channel syndrome, and
COLQ CMS) have a risk of worsening with pyridostigmine and 3,4-
diaminopyridine (3,4-DAP).
• For subtypes of CMS that respond to pyridostigmine (eg, primary
AChR deficiency, RAPSN, fast channel syndrome, CHAT,
glycosylation pathway defects), adjunctive treatment with 3,4-DAP
can be beneficial.
• Limited data suggest that albuterol (salbutamol)
or ephedrine improves muscle strength and mobility in patients
with acetylcholine receptor deficiency caused by CHRNE mutations.
• Albuterol (salbutamol) or ephedrine can be used to treat CMS
caused by DOK7 and COLQ mutations.
• Fluoxetine, quinidine, or quinine may be used to treat slow channel
syndrome

• The cardinal feature of myasthenia gravis is
fluctuating skeletal muscle weakness, often with
true muscle fatigue.
• The fatigue is manifest by worsening contractile
force of the muscle, not a sensation of tiredness.
• Many clinicians think (erroneously) that fatigue
without weakness is consistent with myasthenia.
• Patients present with complaints of specific
muscle weakness and not generalized muscle
fatigue.

• Patients typically have fluctuating weakness and fatigue of
the specific muscle groups affected.
• The weakness may fluctuate throughout the day, but it is
most commonly worse later in the day or evening, or after
exercise.
• Early in the disease, the symptoms may be absent upon
awakening.
• Often, as the disease progresses, the symptom-free
periods are lost; symptoms are continuously present but
fluctuate from mild to severe.
• When present, this fluctuation in symptoms is an important
feature that can distinguish myasthenia gravis from other
disorders that also may present with weakness, such as
myopathy or motor neuron disease.

 More than 50 % of patients present with ocular
symptoms of ptosis and/or diplopia.
 Of those who present with ocular manifestations, more
than half will develop generalized disease within two
years.
 Many of the patients who present without ocular
manifestations develop ptosis or diplopia at some
point in the course.
 Approximately 15 % of patients present with bulbar
symptoms. These include dysarthria, dysphagia, and
fatigable chewing.
 Less than 5 % present with proximal limb weakness
alone

Ocular muscles
• Weakness of the eyelid muscles can lead to ptosis, the degree of which can be
quite variable throughout the day.
• It may switch from one eye to the other over time.
• The ptosis may start bilaterally and improve in one eye, resulting in unilateral
ptosis.
• In addition, ptosis may start unilaterally and then become bilateral. At times,
it may be so severe as to occlude vision.
• The extraocular muscles are also often involved. This produces binocular
diplopia that disappears when the patient closes or occludes one eye. It may
be horizontal or vertical. At the onset, this is sometimes sensed as
intermittent periods of blurred vision before the diplopia is evident.
• On examination, eye movements are often weak in a pattern that does not
conform to the anatomy of one nerve or muscle. They may also be weak in a
pattern that simulates another disorder, such as an isolated oculomotor
neuropathy, an internuclear ophthalmoplegia (INO), or a vertical gaze paresis.
• The pupils are always spared in myasthenia gravis, helping in the
differentiation from other disorders.
• The ptosis may increase with sustained upward gaze or by holding up the
opposite eyelid with the examiner's finger (curtain sign).

• It has been proposed that subtle alterations in the function
of extraocular muscles are more likely to produce
symptoms than in limb muscles, and that the levator
palpebrae, under constant activation during eye opening,
may be more susceptible to fatigue.
• Patients with OMG are more likely to be seronegative for
acetylcholine receptor antibodies (AChR-Ab) than patients
with GMG.
• Extraocular muscles (but not the levator palpebrae) are
unique in their expression of fetal acetylcholine receptors
at the neuromuscular junction; however, there is no
evidence for specific immunologic targeting of this
receptor.

• OMG is characterized by ptosis and oculomotor paresis.
• Some patients also have mild orbicularis oculi weakness.
• This triad, ptosis, oculomotor paresis, and orbicularis oculi
weakness, should prompt an evaluation for MG.
• Signs and symptoms of OMG are characterized by
fluctuating, fatigable weakness.
• Most patients note ocular symptoms that worsen as the
day progresses or with tasks such as driving.
• Patients may report that they have mild or no symptoms
upon wakening.
• The examination may elicit signs of fatigable levator and
extraocular muscle weakness.

Ptosis
• Ptosis is often unilateral or asymmetric on
presentation.
• A historical pattern of ptosis alternating from one
side to the other is nearly always a sign of OMG.
• Old photos may help to determine if ptosis is new
or longstanding.
• Measurements of the eyelid position and levator
palpebrae muscle function using standard
methods help to identify and quantify weakness
as well as fluctuations associated with fatigue.

Examination for eyelid fatigue
• If the ptosis fluctuates throughout the examination,
then evidence for fatigability of the levator muscle is
present.
• Evidence for fatigue can also be elicited (none are
specific for OMG):
– sustained upgaze for one to two minutes.
– Ask to sustain downgaze briefly and then make a fast eye
movement, lid appears to twitch.
– Eyelid "curtaining" occurs when the more ptotic eyelid is
passively lifted above the iris.
– A "rest (two to five minutes) test" looks for improvement
in baseline ptosis.

• Ice pack test (one minute test): sensitivity: 80
%, not diagnostic but can help to raise
suspicion for myasthenia.

DIPLOPIA
• Binocular diplopia (diplopia that is present only with both
eyes open) is a prominent feature of OMG when
ophthalmoparesis is present.
• At presentation, OMG may involve individual or multiple,
bilateral ocular motor muscles.
• For patients with medial or lateral recti muscle
involvement, diplopia will be binocular and horizontal.
• If the superior or inferior recti or the oblique muscles are
involved, then there will be a vertical or diagonal diplopia.
• Every ocular motility disorder (isolated nerve palsies and
even central nervous system brainstem pathways, such as
internuclear ophthalmoplegia) has been described in OMG.

RED GLASS TEST
• A translucent red glass is placed over one eye of the patient while
the patient is looking at a light.
• By doing so, the patient will see one red light and one white light,
and the relationship of the two lights allows the examiner to
determine the type of ocular misalignment that is causing the
double vision.
• For instance, when the red glass is placed over the right eye and
the patient reports that the red light is to the right of the white
light, then the eyes are directed toward each other, as noted with
lateral rectus weakness of either eye.
• The red glass can be made with parallel translucent cylinder lines,
called a Maddox rod, and with the same technique, a patient will
see a red line and a white light.
• The findings help identify the misalignment but cannot identify
whether both eyes or one eye is weak, but the pattern can narrow
down the muscles involved after testing in multiple positions of
gaze (ie, up, right, left, down)

• Lagophthalmus: failure of the eye to fully close, is rare in
OMG.
• However, some weakness of the orbicularis oculi is often
demonstrable when the examiner attempts to open the
eyes against forced eyelid closure, nearly impossible in the
intact patient.
• The "peek-a-boo" sign of lagophthalmus after prolonged
forced eyelid closure suggests fatigue in this muscle.
• Pupillary involvement is generally not seen in OMG.
• Descriptions of pupil abnormalities such as constrictor
fatigue with repeated light stimulation as well as
accommodation fatigue are findings that are not elicited in
practice by most examiners.

DIFFERENTIAL DIAGNOSIS
• The differential diagnosis of signs and symptoms associated
with OMG depends on the specific symptoms cluster:
●Isolated ptosis
●Isolated ophthalmoparesis
●Ptosis and ophthalmoparesis
●Ptosis, ophthalmoparesis, and other signs or symptoms of
bulbar weakness
Thyroid ophthalmopathy
Chronic progressive external ophthalmoplegia
Muscular dystrophy
Brainstem and motor cranial nerve pathology

DIAGNOSTIC TESTS
• The diagnosis of OMG can often be made on a
clinical basis when the history and
examination findings are classic

Serum antibody studies
• While more than 85 % of patients with GMG have serum
antibodies against the acetylcholine receptor (AChR-Ab), the
sensitivity of AChR-Ab testing in OMG may be as low as 45 to 60 %.
• This is the most specific test for MG; no false positives have been
reported.
• Some patients with GMG who are seronegative for AChR-Ab have
antibodies against the muscle-specific tyrosine kinase (MuSK).
• Once thought to be unassociated with OMG, MuSK antibodies have
been detected in patients with OMG in a few case reports.
• A number of reports have linked low-density lipoprotein receptor-
related protein 4 (LRP4) antibodies with GMG.
• In three reported cases of OMG, patients who were found to be
seronegative for both AChR-Ab and MuSK were found to have
positive LRP4 antibodies.

Electrophysiology
• Repetitive nerve stimulation : RNS studies
demonstrate decrement in the amplitude of the
compound muscle action potential after repetitive
stimulation of the motor nerve to that muscle.
• The orbicularis oculi may be studied in patients with
OMG.
• Among patients with GMG, the sensitivity of RNS is
greater than 70 %, By contrast, among patients with
OMG, the sensitivity 15-45 %.
• The specificity is 89 %; both false negatives and false
positives do occur.

Single-fiber EMG
• SFEMG identifies abnormal neuromuscular transmission by measuring
temporal variability in the firing of adjacent motor nerve fibers from a single
motor unit, a phenomenon called "jitter."
• SFEMG is more sensitive than RNS and may identify electrophysiologic
abnormalities in clinically strong muscles.
• Depending on which and how many muscles are examined, the sensitivity of
SFEMG for OMG is between 63 to 100 %.
• Evaluation of the orbicularis oculi and the superior rectus levator palpebrae
complex increase the sensitivity in patients with OMG to over 95 %.
• Abnormal jitter is not specific for myasthenia.
• However, while patients with MG generally have an otherwise normal standard
electromyography (EMG) examination, other neuromuscular diseases that
increase jitter do not. An exception may be in differentiating patients suspected
of OMG from those with chronic progressive external ophthalmoplegia (CPEO).
• CPEO is often, but not always, associated with a myopathic pattern on EMG,
and SFEMG does not clearly help distinguish these two entities.
• Two reports give conflicting data: in the presence of a normal needle EMG
examination, one showed abnormal SFEMG in CPEO, while the other did not

• Patients with suspected OMG should also have a chest computed
tomography (CT) scan to rule out thymoma and thyroid function
tests to rule out associated thyroid dysfunction.
• 2/3rd will go on to develop signs and symptoms of extremity
weakness and other bulbar muscle weakness, while 1/3rd will have
pure OMG.
• Most (78 %) of those who will develop generalized MG (GMG) do so
within the first year, and virtually all (94 %) will do so by three
years.
• A normal single-fiber electromyography (SFEMG) study may be
helpful in stratifying risk of generalization.
• In one study of 37 patients with OMG followed for two years, 82 %
of those with normal SFEMG in the extensor digitorum communis
persisted with isolated OMG, whereas 58 % of those with an
abnormal study developed GMG.

• Assistive devices (ptosis crutches and lid adhesive devices) can aid
in the treatment of ptosis pending a response to
acetylcholinesterase inhibitors or immunosuppressive therapy.
• Use of lubricating drops to prevent corneal dryness and exposure
keratopathy.
• An eye patch, opaque contact lens, or occlusion of an eyeglass lens
are simple ways to eliminate diplopia.
• Prism lenses offer another nonpharmacologic alternative for
patients with diplopia.
• If the ophthalmoparesis is stable over several weeks or months,
prism lenses may minimize diplopia. However, fatigability and
significant variability of eye movements will limit the benefit of
prisms in patients with OMG until stabilization occurs.

Surgery for ptosis and diplopia
• Surgical correction can be performed on patients with stable ptosis.
• Recurrence of ptosis for patients who do not demonstrate stability prior to surgery
is common due to the nature of myasthenia.
• The optimal duration of stability prior to surgery is unknown, although there are
some indications that three to four years of stability prior to ptosis repair is
appropriate.
• Extraocular muscle resection and recession can be performed on patients with
stable ophthalmoparesis.
• Similar to the situation for ptosis, recurrence of diplopia for patients who do not
demonstrate stability prior to surgery is common.
• The optimal duration of stability prior to surgery is unknown; shorter durations of
stability (five to six months) prior to strabismus surgery are advocated compared
with ptosis surgery, but follow-up data on these patients are limited.
• Based on natural history data, which indicate that myasthenia has a more stable
course three years after onset, a conservative approach is to consider strabismus
surgery for patients three years after onset of OMG, if deficits have been stable for
at least one year and if they desire surgery and have either failed to respond to
medical therapy or have contraindications for continued medical therapy.

Facial muscles
• Facial muscles are frequently involved and make the
patient appear expressionless.
• Family members may notice that the patient has "lost
his or her smile" as a result of weakness of the
orbicularis oris muscle.
• This transverse smile may be evident on examination.
• When attempting to smile, the patient may produce
the "myasthenic sneer," where the mid-lip rises but the
outer corners of the mouth fail to move.
• Orbicularis oculi weakness is often easily identified on
examination when prying the eyes open during forced-
eye closure.

Neck and limb muscles
• Neck extensor and flexor muscles are commonly affected.
• The weight of the head may overcome the extensors,
particularly late in the day, producing a "dropped-head
syndrome".
• Posterior neck muscles may ache due to the added effort in
keeping the head up with the weakened muscles.
• Involvement of the limbs in myasthenia produces
predominantly proximal weakness similar to other muscle
diseases.
• However, the arms tend to be more often affected than
the legs. In addition to proximal muscles, wrist and finger
extensors and foot dorsiflexors are often involved.

Respiratory muscles
• Involvement of the muscles of respiration produces the
most serious symptoms in myasthenia gravis.
• Respiratory muscle weakness that leads to respiratory
insufficiency and pending respiratory failure is a life-
threatening situation called "myasthenic crisis."
• It may occur spontaneously during an active phase of
the disease or may be precipitated by a variety of
factors including surgery, infections, certain
medications, or tapering of immunosuppression.
• A number of medications can increase weakness in
myasthenia and should be avoided or used with great
caution

Myasthenic crisis
• worsening of myasthenic weakness requiring
intubation or noninvasive ventilation, When this results
in upper airway obstruction or severe dysphagia with
aspiration, intubation and mechanical ventilation are
necessary.
• Increasing generalized or bulbar weakness as a
warning.
• Occasionally, a patient presents with respiratory
insufficiency out of proportion to limb or bulbar
weakness.
• Generalized weakness can mask the usual signs of
respiratory distress.

Cholinergic crisis
• A potential major side effect of excessive
anticholinesterase medication is weakness, which can be
difficult to distinguish from worsening myasthenia gravis.
• This paradoxical weakening with anticholinesterase
medications is called "cholinergic crisis."
• However, cholinergic crisis is rarely if ever seen with
dose limitation of pyridostigmine to less than 120 mg
every three hours.
• Cholinergic crisis is so rare that it should not be the
presumed cause of increasing weakness unless the doses
taken are known to significantly exceed this range.
• Otherwise, even in the presence of cholinergic side
effects, it should be assumed that the patient's
underlying myasthenia gravis is worsening and
appropriate treatment should be initiated.

Clinical course
• Early in the disorder, the symptoms are often transient in many
patients, with hours, days, or even weeks free of symptoms.
• The symptoms may even remit spontaneously for weeks or longer.
• However, the manifestations typically worsen and are more
persistent.
• New symptoms often develop weeks or months later.
• The progression of myasthenia gravis usually peaks within a few
years of disease onset.
• In a case series from the United States of 1976 patients with
myasthenia gravis, the maximum extent of weakness was reached
within two years in 82 percent of patients.
• In another retrospective study of 1152 patients in Italy, the
maximum extent of the disease was seen by three years of onset.

Diagnosis of myasthenia gravis
• BEDSIDE TESTS
• Ice pack test —
– The ice pack test can be used as part of the neurologic
examination in patients with ptosis.
– It is not helpful for those with extraocular muscle weakness.
– The test is based on the physiologic principle that
neuromuscular transmission improves at lower muscle
temperatures.
– In patients with myasthenia, ptosis can be overcome by direct
cooling of the eyelid muscles.
• Ice placed on the closed lid for two minutes, the extent of
ptosis is immediately assessed.
• The sensitivity appears to be approximately 80 percent in
those with prominent ptosis due to myasthenia.

• The injection of edrophonium also potentiates
the muscarinic effects of acetylcholine and is not
without risk, especially in older adults, or those
with cardiac disease or bronchial asthma.
• These medical conditions are relative
contraindications for the edrophonium test.
• Patients frequently develop increased salivation
and mild gastrointestinal cramping.
• More seriously, symptomatic bradycardia or
bronchospasm can occur.

SEROLOGIC TESTING
• Autoantibodies against the
– Acetylcholine receptor (AChR-Ab) (85%), or
– Against a receptor-associated protein, muscle-
specific tyrosine kinase (MuSK-Ab)(8%).
– Low density lipoprotein receptor-related protein 4
(LRP4) (1%).
– Seronegative: 6%.
• It is not helpful to follow the AChR-Ab levels as
a marker for improvement.

• Ideally, serologic testing for AChR-Ab should be performed
prior to initiating immune modulating therapy for
myasthenia gravis, as such therapy can sometimes lead to
apparent seronegativity.
• MuSK antibodies are present in 38 to 50 percent of those
with generalized myasthenia gravis who are AChR-Ab
negative.
• One consistent finding is that patients with AChR-Ab
negative myasthenia gravis and MuSK antibodies have a
much lower frequency of thymic pathology than patients
with AChR-Ab positive myasthenia.
• Thymic hyperplasia is frequent in AChR-Ab positive
myasthenia, but this pathology is much less frequent in the
MuSK-Ab positive group.

• LRP4 antibodies patients tend to be younger,
more often are female, and have milder
disease, no association with thymic pathology.
• Patients with seronegative myasthenia gravis
are more likely to have purely ocular disease.
• There is also a trend for those with
generalized seronegative myasthenia to have a
better outcome after treatment.

RNS
• The test is performed by placing the recording electrode over the endplate
region of a muscle and stimulating the motor nerve to that muscle.
• The nerve is electrically stimulated 6 to 10 times at low rates (2 or 3 Hz).
• The compound muscle action potential (CMAP) amplitude is recorded
from the electrodes over the muscle after electrical stimulation of the
nerve.
• In normal muscles, there is no change in CMAP amplitude with RNS.
• In myasthenia there may be a progressive decline in the CMAP amplitude
with the first four to five stimuli (a decremental response).
• An RNS study is considered positive (ie, abnormal) if the decrement is
greater than 10 percent.
• It is important to sample distal and proximal muscle to maximize the yield.
• Distal muscles are technically easier, but they have a lower diagnostic
sensitivity.
• If possible, clinically weak muscles should be included as well.
• To maximize the sensitivity, the muscles tested should be warm, and
acetylcholinesterase inhibitors should be held for 12 hours before the
study.

• A suitable RNS study usually consists of low-rate (at 2 or 3 Hz)
stimulation with one or two trains of 6 to 10 stimuli and CMAP
recordings at rest, followed by an exercise protocol.
• In the exercise protocol, the patient is asked to exercise the muscle
maximally for 30 to 60 seconds.
• A train of stimuli is performed immediately after exercise.
• A repair of the CMAP decremental response (a smaller percent
decrement compared with the decrement seen at rest) is
commonly seen, reflecting postexercise or postactivation
facilitation.
• An additional train of stimuli is delivered at one, three, and five
minutes after exercise.
• This may result in a larger decrement than seen at rest, termed
postexercise or postactivation exhaustion.
• This exercise protocol may increase the sensitivity of RNS by an
additional 5 to 10 percent.

• A decremental response is not specific for
myasthenia gravis.
• Decrements may be seen in other disorders of
neuromuscular transmission (Lambert-Eaton
myasthenic syndrome or botulism) and motor
neuron disease.
• These disorders should not cause electrodiagnostic
confusion when combined with studies looking for
presynaptic disorders of neuromuscular
transmission and standard needle
electromyography.

Single-fiber electromyography
• SFEMG is more technically demanding than RNS and is
less widely available, but it is the most sensitive
diagnostic test for myasthenia gravis.
• This technique allows simultaneous recording of the
action potentials of two muscle fibers innervated by
the same motor axon.
• The variability in time of the second action potential
relative to the first is called "jitter."
• Any disorder, such as myasthenia gravis, that reduces
the safety factor of transmission at the neuromuscular
junction will produce increased jitter.
• To maximize the sensitivity, a limb and facial muscle
may be studied.

• Abnormal jitter is not specific for myasthenia.
• It may be abnormal in motor neuron disease,
polymyositis, peripheral neuropathy, Lambert-Eaton
myasthenic syndrome, and other neuromuscular
disorders.
• However, it is specific for a disorder of neuromuscular
transmission when no other abnormalities are seen on
standard needle EMG examination.
• The exception may be in differentiating patients
suspected of ocular myasthenia gravis from those with
Kearns-Sayre syndrome (KSS) causing chronic
progressive external ophthalmoplegia (CPEO).

RNS
• Repetitive nerve stimulation (RNS) represents a modification
of conventional motor NCS.
• The interval between repeated motor nerve stimulations is
varied to manipulate the neuromuscular physiology.
• Slow RNS is designed to maximally stress the neuromuscular
junction safety factor.
• Since it takes approximately one to two seconds to replete
the primary pool of presynaptic acetylcholine vesicles, slow
rates of repetitive stimulation (1 to 5 Hz) deplete the number
of available quanta for release with subsequent
depolarizations.
• The percent of the remaining quanta released with the next
stimulation will be determined by the presynaptic calcium
concentration.

• RNS of 1 to 5 Hz allow for the re-equilibration of the presynaptic
calcium concentration between stimulations so with the smaller
primary pool, a smaller number of quanta will be released with
each subsequent stimulation for at least the first five or six stimuli
in a train.
• In the normal neuromuscular junction, this reduced amount of
acetylcholine is still adequate to reliably depolarize the muscle
fiber.
• However, in pathologic states where the safety factor for
neuromuscular junction transmission is considerably reduced, some
fibers will fail to depolarize in the later stimuli of a train and the
compound muscle action potential (CMAP) amplitude will drop,
which is referred to as a decrement.
• The presence of this decremental response on RNS has been the
neurophysiologic hallmark of myasthenia gravis.

TECHNIQUE
• The technique of RNS incorporates the surface stimulation and
surface recording procedures used in routine motor nerve conduction
studies.
• The CMAP obtained after single supramaximal stimulation represents
the summation of the electrical activity from the individual muscle
fibers of the entire muscle.
• The negative peak area (or alternatively the amplitude) is a reflection
of the number of muscle fibers activated.
• Before delivering the RNS train, the joint is immobilized if possible.
• As an example, taping the fingers together or applying a hand brace
can prevent finger movement, and thus movement artifacts, when
stimulating the ulnar nerve.
• Some muscles are not amenable to immobilization, such as the facial
or trapezius muscles.
• The stimulator is taped in position and held to prevent movement of
the stimulating electrode, which leads to a submaximal stimulation
and a reduction of the CMAP amplitude or area.
• This problem is one of the major causes of inaccurate data.

Slow RNS
• With slow RNS, a train of five to nine stimuli is delivered to the
peripheral nerve and the resultant CMAPs are sequentially
recorded.
• A slow rate (1 to 5 Hz) causes depletion of the immediately
available acetylcholine pool without increasing presynaptic calcium.
• This procedure reduces the neuromuscular junction transmission
safety factor and is usually used to study patients suspected of
having a postsynaptic neuromuscular junction disorder such as
myasthenia gravis. The sensitivity of the procedure is further
enhanced by retesting the muscle after a period of tetanic
stimulation.
• Electrical high-frequency (tetanic) stimulation is extremely
uncomfortable for the necessary 45 to 60 seconds, but the same
effect is obtained in the cooperative patient by one minute of
maximal isometric exercise specifically in the muscle being tested.

• Although initially inducing facilitation (post-tetanic
potentiation) by an increase in the presynaptic calcium and
increased mobilization of the acetylcholine pool, this effect
wanes after two to four minutes, and the depletion of
presynaptic acetylcholine reduces the neuromuscular
junction safety factor, increasing the decrement in a
subsequent train of five to nine stimulations (post-tetanic
exhaustion).
• While several different protocols have been suggested, we
suggest RNS testing with trains of five to nine potentials
before exercise and after one minute of maximal isometric
activation at one-half, one, two, and four minute intervals.
• A typical series of RNS stimuli trains is demonstrated for
both a normal patient and a patient with myasthenia gravis.

• The degree of decrement is usually expressed as the percent of the
decrease in amplitude (A) or area of the lowest response (usually
the fourth or fifth) relative to the first potential.
• Percent decrement = (A 1st response – A 4th or 5th response) ÷ A
1st response
• A reproducible decrement of >10 percent is considered abnormal
in most muscles.
• A notable exception is the tibialis anterior, where a decrement of
>20 percent is recommended as the abnormal cut-off value.
• One report found that the optimal decrement of RNS in facial
muscles was 7 to 8 percent.
• If there is any question of the quality of the data as described in the
next section, a 20 percent decrement is more conservative.

• If the stimulator moves during the course of
testing, it can deliver a submaximal stimulus and
a pseudodecrement may occur.
• Alternatively, the resulting waveforms may have
considerable wave-to-wave variability in a
seemingly random pattern

• In contrast to the gradual decline in amplitude
and area typical of a biologically significant
decrement.
• So, hold it throughout the course of testing, even
between trains of stimuli, to prevent movement.

Patient movement or electrode contamination alters the interface between skin
and recording electrode and between the electrode and the signal generator (the
muscle).
Induce instability in the baseline of the CMAPs
Acetylcholinesterase inhibitors should be discontinued prior to study, Four hours is
probably adequate, but 12 or more hours before the RNS study is preferred.
Reduced temperature increases the safety factor of neuromuscular transmission
and thus reduces the decrement, resulting in a false-negative result.

• The maximal decrement is usually present
between the first and either the fourth or fifth
potential in a series.
• In the sixth to ninth potentials, there is either a
mild increase in amplitude/area or a leveling off,
most likely due to the eventual repletion of the
acetylcholine primary pool.
• This pattern is characteristic of myasthenia gravis.

• The final test for the
accuracy of a decrement is
its repair following brief
high-intensity isometric
exercise.
• This can be done after a
single RNS train
demonstrates a decrement
or after the occurrence of
post-tetanic exhaustion
where 15 seconds of a
maximal isometric
contraction followed by a
train of five supramaximal
stimuli will demonstrate
the resolution of the
decrement by increasing
the presynaptic calcium
concentration and thus the
quanta release

Nerve selection for slow RNS
• The ulnar nerve is most commonly tested, with abductor digiti minimi
muscle.
• Radial nerve innervated extensor indicis proprius muscle, is technically
straightforward with greater sensitivity compared with the abductor
digiti minimi.
• The probability of an abnormal study is higher in more proximal
muscles.
• If clinically weak, the axillary nerve (deltoid muscle recording) and the
peroneal nerve (tibialis anterior) also be tested.
• The spinal accessory nerve recording over the trapezius muscle is
particularly uncomplicated and would be recommended .
• Highest yield with RNS is typically obtained by studying a facial muscle
(orbicularis oculi muscle-MC), also the trigeminal nerve (masseter)
and other segments of the facial nerve (nasalis, orbicularis oris) are
also useful at times

Slow RNS protocol
• Slow RNS is performed at 2 or 3 Hz using trains of nine stimuli at rest.
• If a decrement of ≥20 percent is present, 10 seconds of maximal isometric
exercise is performed to see whether the decrement repairs.
• If it does not, another 10 seconds of exercise is recommended.
• No further RNS testing of that nerve is necessary if the decrement is >20
percent, repairs with exercise, and contains the other physiologic
characteristics of decrement.
• If not, testing for postexercise exhaustion is performed with one minute of
maximal isometric exercise, followed by trains of nine stimuli every minute
for at least 4 minutes and at times 6 to 8 minutes.
• Concentric needle examination of several muscles is also suggested at a
minimum, including any muscle with an abnormal RNS, since any illness
with reinnervation and several different types of muscle disease can have
a decrement on slow RNS.

Conditions that have been noted to
induce decremental responses
●Lambert-Eaton myasthenic syndrome (LEMS)
●Radiculopathy
●Motor neuron disease
●Peripheral neuropathy
●Polymyositis
●Some myopathies (McArdle disease, paramyotonia
congenita, hyperkalemic periodic paralysis, etc)
●Medication effects (especially d-penicillamine,
aminoglycosides, and nondepolarizing neuromuscular
blocking agents)
●Botulism
●Organophosphate poisoning

Rapid RNS protocol
• For suspected LEMS, the abnormalities are usually evident in all muscles,
so the abductor digiti minimi (ulnar nerve) is chosen for study.
• The supramaximal CMAP baseline is recorded, followed by a slow RNS
train of five stimuli at 2 to 3 Hz.
• Next, 10 seconds of maximal isometric exercise is performed, if the patient
is cooperative, and the CMAP repeated.
• If unable to activate the muscle voluntarily, a high-frequency RNS is
delivered at 20 Hz for two to three seconds, after preparing the awake
patient for the significant expected discomfort.
• If unclear, a second trial at another readily accessible & weak muscle is
recommended.
• The procedure for suspected botulism is similar.
• However, as described above, the abnormalities are often more subtle
with botulism than with LEMS, and the examination of a weak muscle is
more important

Rapid RNS
• In disorders of the presynaptic terminal of the neuromuscular
junction, where the number of released vesicles is markedly
reduced, high-frequency (tetanic) stimulation can markedly
increase the release of acetylcholine and thus the size of the CMAP.
• The clinical correlate is a corresponding increase in muscle power.
• Therefore, in disorders of impaired presynaptic acetylcholine
release, the defining neurophysiologic pattern is a reduced CMAP
amplitude in rested muscle that significantly increases with tetanic
stimulation.
• The reduced baseline CMAP amplitude typically involves the great
majority of motor nerves, even recording over strong muscles, and
the absolute value is usually well below the normal range.
• The most frequently encountered clinical disorder of presynaptic
function is LEMS.

• Tetanic stimulation is
most easily accomplished
by voluntary maximal
isometric muscle
contractions or RNS at 10
to 50 Hz can be employed
in obtunded patients.
• The typical clinical
protocol for suspected
LEMS is 15 seconds of
maximal isometric
contraction of the target
muscle, preceded and
followed by a
supramaximal CMAP.

• The alternative
procedure is high-
frequency electrical
repetitive stimulation
(20 to 50 Hz) for 1 to
10 seconds, which is
consistently reported
to be uncomfortable.
• Amplitude increases of
100 % are traditionally
considered to be
diagnostic of LEMS,
but a compelling case
has been made for the
more liberal value of
60 percent.

• Although mild increments can
be seen from facilitation and
pseudofacilitation, values at
this level are clearly abnormal
and exclude normal
phenomena as well as
disorders of peripheral nerve,
postsynaptic neuromuscular
junction, or muscle. At slow
rates of RNS, decremental
responses are also often
present in presynaptic
neuromuscular junction
disorders due to the
progressive reduction of
quantum release from a
progressive decline in the size
of the available acetylcholine
vesicle pool and the static
calcium concentration.

SINGLE-FIBER ELECTROMYOGRAPHY
• Conventional monopolar (A) or concentric needle (B)
electrodes record potentials that represent the
summated compilation of individual muscle fibers firing
in near synchrony.
• SFEMG is performed with a specially configured
electrode that allows the recording of a small number of
individual muscle fiber potentials within the same motor
unit.
• Although this technique has several applications, the
primary purpose is the electrophysiologic evaluation of
the neuromuscular junction and the determination of
"jitter," which represents the variability of the interval
between stimulation and depolarization of a single
muscle fiber with stimulated SFEMG, or between two
single muscle fibers from the same motor unit with
conventional SFEMG (figure 5). As described below,
SFEMG is the most sensitive electrodiagnostic procedure
for the determination of myasthenia gravis.

JITTER
• When single muscle fibers from the same motor unit are activated
or stimulated repetitively, there is a very small variability in the
latency of each response.
• This is due primarily to changes in the amplitude and slope of the
endplate potential (EPP) on the postsynaptic membrane; the
contributions from the peripheral nerve or muscle fiber
components of the motor unit are negligible.
• This variability in the latency is termed "jitter."
• To measure jitter in the clinical setting, the recording electrode is
positioned to record two or more muscle fibers simultaneously
using the techniques described below.
• In the absence of a disorder of the peripheral motor nerve, any
variability in the interpotential latency difference, referred to as the
"interpotential interval" (IPI), would be due to changes in the time
of neuromuscular junction transmission.

• The conventional method of expressing jitter is as the
mean value of consecutive differences (MCD) rather than
the mean IPI.
• This calculation compensates for small changes in the
electrode position during the study.
• MCD = ([IPI1 – IPI2] + . . . . . . . . . . + [IPIn–1 – IPIn]) ÷ (n – 1)
• When the neuromuscular junction safety factor is reduced,
there will be times when the EPP may be inadequate to
depolarize the muscle fiber, and its failure to contract is
called blocking.
• The clinical correlation of a significant degree of blocking is
muscle weakness. Muscles with increased jitter but little or
no blocking usually have normal strength.

• In evaluating the results of a SFEMG study, it
must be remembered that jitter is altered by
many factors, including:
●Temperature
●Firing rate
●Neuromuscular blocking agents
●Acetylcholinesterase inhibitors
●Ischemia
●Reinnervating illnesses
●Neuromuscular junction disorders

Needle electrode
• A small recording surface is present 3 mm from the tip of the
electrode on the side of the shaft.
• This allows for a selective extracellular recording field adjacent to a
small number of muscle fibers.
• There is an exponential drop of the recorded motor fiber amplitude
with increasing distance from the recording site.
• This is a critical characteristic since it minimizes the contamination
from adjacent muscle fibers.
• The active recording surface of the SFEMG electrode is 25 to 30
micron with a functional recording field of approximately 300
micron from the uptake area and a 200 micron interelectrode
distance. In comparison, a conventional concentric needle electrode
has an exposed surface of 150 by 600 micron with a recording
radius of approximately 1 mm.
• Preliminary studies comparing the specialized SFEMG electrode
with conventional concentric or monopolar recording electrodes in
the diagnosis of myasthenia gravis have yielded similar results

Single-fiber potential
• The single-fiber potential is dominated by high-
frequency components.
• This allows the low-frequency filter to be set
high, minimizing the volume-conducted
components of more distant motor units.
• The biphasic spike has a rise time range of
approximately 75 to 200 microsecond and
duration of approximately 1 microsecond.
• The amplitude varies from 200 microV to 10 mV,
but it is usually in the 1 to 5 mV range.

Recording procedures
• Recording the single-fiber potentials requires that the muscle be activated in
a controlled manner. Traditionally, this has been accomplished with a
sustained weak voluntary contraction.
• Stimulated SFEMG has gained acceptance as an accurate alternative that is
usually quicker and easier for the patient, but offers some novel technical
considerations.
– With voluntary contraction SFEMG, the patient weakly activates the relevant
muscle, most often the extensor digitorum communis, and the recording
electrode is inserted. The needle is slowly rotated or advanced to maximize the
muscle fiber potentials with the trigger set on the initial positivity of the action
potential. The key is making small movements of the recording electrode and
rotating the shaft until two or more suitable time-locked potentials are present.
A single-fiber potential will have an identical repeating waveform since it
depolarizes in an all-or-none manner while a waveform with a varying
configuration is likely a summated potential of two or more single-fiber
potentials and is excluded.
– Stimulated SFEMG is performed by stimulating distal nerve twigs, often
intramuscular, with a needle electrode and recording the individual muscle fiber
depolarizations with the same recording techniques and recording electrode as
described above when utilizing voluntary activation.

• Stimulated SFEMG is technically more difficult than the
conventional voluntary procedure. As only one muscle fiber is
studied at a time, the stimulus-to-response interval is measured
rather than an IPI. Multiple fibers can be recorded at a time, but
each involves a separate analysis. Any waveform peak meeting the
appropriate criteria can be used, often allowing for the evaluation
of numerous fibers in a single tracing. The normal mean MCD in
stimulated SFEMG is approximately two-thirds the value for
voluntary activation, since the jitter is occurring in only a single
fiber instead of both fibers of a pair. The top normal mean MCD for
the extensor digitorum communis (stimulated) is 25 microsecond.
• Stimulated SFEMG is useful in many clinical situations, and is
particularly appropriate for the study of facial muscles since steady
prolonged voluntary activation of these muscles is difficult. Other
applications vary with the clinical setting.

Criteria for abnormality
• Jitter varies considerably between different muscles. Standard values have been
established for many muscles; we generally use the SFEMG reference values
published in 1994 by the Ad Hoc Committee of the AAEM Single Fiber Special
Interest Group.
• The best studied muscle for SFEMG is the extensor digitorum communis, which is
well suited to the difficult process of minimal voluntary activation. Three pieces of
data are usually considered in the interpretation of a study:
 The jitter, expressed as the MCD
 The percent of pairs whose jitter exceeds the upper limit of normal for the muscle under study
 The percent of blocked fibers
• Since blocking represents the most severe form of neuromuscular junction
dysfunction, it is rarely seen without a clear increase in jitter. For the extensor
digitorum communis muscle, jitter (mean MCD) >35 microsecond is generally
considered abnormal, as is >10 percent of pairs with MCD values >55 microsecond
or >10 percent of pairs with any fiber blocking. The same values for stimulated
SFEMG of the extensor digitorum communis are mean MCD >25 microsecond or
>10 percent of pairs with MCD values >40 microsecond. Values for the orbicularis
oculi muscle are 20 and 30 microsecond, respectively .
• Jitter values remain fairly stable until roughly 60 years of age when the normal
values in some muscles need to be adjusted

Utility of SFEMG
• SFEMG is the most sensitive electrodiagnostic procedure for the
determination of myasthenia gravis. It is more sensitive than RNS because
neuromuscular junction abnormalities that do not induce muscle fiber
blocking (decrement) can still demonstrate important increases in jitter.
Consequently, there are often significant jitter abnormalities in muscles
without weakness.
1. In a pattern similar to RNS, the sensitivity of SFEMG is directly related to the
severity of myasthenia. As an example, one report found that SFEMG of the
extensor digitorum communis muscle was abnormal in 60 percent of
patients with ocular myasthenia gravis and 89 percent with generalized
myasthenia gravis. These values increased to 97 and 99 percent,
respectively, if SFEMG of any of three tested muscles were used as the
criteria (extensor digitorum communis, frontalis or orbicularis oculi). Other
studies have reported similar values. The yield has been consistently highest
in weak muscles and/or facial muscles. Even in pure ocular myasthenia
gravis, SFEMG in the extensor digitorum communis (an unaffected muscle) is
abnormal at the time of presentation in the majority of patients.

2. Some have suggested the subgroup of patients with MuSK antibody-positive
myasthenia gravis may be less likely to have abnormal SFEMG in the
extensor digitorum communis muscle than patients with acetylcholine
receptor antibody positive myasthenia gravis or other patients with
seronegative myasthenia gravis, but this was not confirmed by others. All
three groups have had approximately the same frequency of abnormalities
with SFEMG in the orbicularis oculi muscle.
3. Voluntary SFEMG may have a greater sensitivity for the diagnosis of
myasthenia gravis than stimulated SFEMG in the extensor digitorum
communis. However, methodologic problems limit the value of these data,
and further investigation is necessary.
4. In two reports, SFEMG of the extensor digitorum communis in patients with
ocular myasthenia gravis did not predict progression to generalized
myasthenia gravis, although in the one prospective study, those patients
with a normal SFEMG were less likely to subsequently develop generalized
myasthenia.
5. Although there is a tendency for increased jitter with increasing stimulation
rates in some patients with myasthenia gravis, this is not a consistent or
predictable finding and it is not useful as a diagnostic test

Overview of therapies
●Symptomatic treatment (acetylcholinesterase
inhibition) to increase the amount of acetylcholine
(ACh) available at the neuromuscular junction
●Chronic immunosuppressive therapies
(glucocorticoids and nonsteroidal
immunosuppressive agents) to target the underlying
immune dysregulation
●Rapid but short-acting immunomodulating
treatments (therapeutic plasma exchange and
intravenous immune globulin [IVIG])
●Surgical treatment (thymectomy)

Treatment goals and response
assessment
• To render patients minimally symptomatic or better while
minimizing side effects from medications.
• MG is a chronic but treatable disease, and many patients
can achieve sustained remission of symptoms and full
functional capacity.
• The response to pyridostigmine and other therapies is
judged by improvement in the clinical symptoms and
neurologic deficits on examination.
• Baseline neurologic function and deficits should be
documented at the start of therapy and monitored for
change over time as therapies are added or tapered.
• In general, following acetylcholine receptor (AChR) or other
antibody levels as a marker for treatment response in MG
is not recommended.

• Fluoroquinolone (such as ciprofloxacin and levofloxacin) antibiotics may exacerbate
muscle weakness in some patients with MG
• Aminoglycosides should be avoided and only used if absolutely necessary with
close monitoring.
• Telithromycin has been associated with severe exacerbations or unmasking of MG
in several case reports, often within two hours of the first dose.
• Neuromuscular blocking agents may be necessary for anesthesia or intubation, but
their use delays emergence from anesthesia, recovery of muscle strength, and
weaning from mechanical ventilation.
• Intravenous local anesthetics (eg, lidocaine, procaine) are unlikely to cause
significant neuromuscular weakness in otherwise healthy adults, but they can
potentiate the effects of neuromuscular blocking agents experimentally.
• Magnesium sulfate is relatively contraindicated because magnesium has a
significant inhibitory effect on ACh release.
• Penicillamine should be avoided in patients with MG because it can induce MG
• Programmed cell death 1 (PD-1) inhibitors, such as nivolumab and pembrolizumab,
are used as immunotherapy in certain cancers (eg, metastatic melanoma and non-
small cell lung cancer). These drugs enhance immune responses and have been
reported to trigger autoimmune MG.
• Certain cardiac drugs, such as all beta blockers and procainamide, should be used
with caution.
• Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) have
occasionally been reported to unmask or exacerbate MG.
• However, statins are not contraindicated in patients with MG and should be used in
those with appropriate cardiovascular indications and monitored.

INITIAL SYMPTOMATIC THERAPY
• Pyridostigmine — The initial therapy for most patients with mild to moderate
MG is an oral Ach inhibitor (ie, anticholinesterase), usually pyridostigmine.
• Neostigmine is available in an oral form but not commonly used.
• Ach inhibitors retard the degradation of acetylcholine (ACh) that occurs by
enzymatic hydrolysis in the neuromuscular junction, As a result, the effect of
ACh is prolonged, leading to a variable improvement in strength in patients
with MG.
• MuSK)-positive disease have a poor response to anticholinesterase agents.
• Improvement may be mixed; Ex: there may be resolution of neck weakness
and ptosis with persistence of diplopia.
• In general, limb and bulbar symptoms (dysphagia, fatigable chewing, and
dysarthria) respond better to anticholinesterase drugs than the ocular
manifestations (ptosis and diplopia). Diplopia is particularly resistant to
these medications in many patients.
• Acetylcholinesterase inhibitors provide only symptomatic therapy and are
usually not sufficient in generalized MG. Nonetheless, in some patients this
is the only therapy ever needed for good control.

Dose and titration
• Pyridostigminehas a rapid onset of action (15 to 30 minutes) with peak action at
approximately two hours, and its effects last for three to four hours, sometimes
longer.
• Despite its short duration of action, some patients can use it quite effectively with
doses every six / three hours or three times a day to maintain symptomatic
benefit.
– For adults and older adolescents, a common starting dose is pyridostigmine 30 mg
three times a day with meals for two to three days to assess the cholinergic side
effects. For those with excessive cholinergic side effects we add an agent (eg,
oral glycopyrrolate 1 mg with each pyridostigmine dose) to block those bothersome
symptoms.
– For those who tolerate the pyridostigmine well, with or without anticholinergics,
increase the dose by 30 mg increments until we get to a good therapeutic effect or are
limited by side effects. The maximum dose is usually 120 mg every four hours while
awake. An occasional patient may need to take it every three hours while awake, but
never at shorter intervals.
– Almost all adult patients require a total daily dose of ≤960 mg, divided into four to
eight doses.
– For children and younger adolescents, the initial dose is 0.5 to 1 mg/kg every four to six
hours with meals.
– This can be titrated up slowly based on the therapeutic response and side effects. The
maximal daily dose is 7 mg/kg per 24 hours divided in five to six doses.

• No single pyridostigmine dosing schedule fits all
patients.
• Most adult patients who respond do so in the range of
60 to 90 mg every four to six hours while awake.
• Some adults require as much as 120 mg every three to
four hours while awake.
• When a patient has significant persistent weakness
despite the use of pyridostigmine in sufficient doses,
or the side effects preclude effective dosing, then
immunosuppressive therapy is generally warranted.

CHOLINERGIC SIDE EFFECTS
• Adverse effects
of pyridostigmine are mostly
due to the cholinergic
properties of the drug.
• Can be dose-limiting in many.
• The most bothersome
muscarinic side effects include
abdominal cramping and
diarrhea, increased salivation
and bronchial secretions,
nausea, sweating, and
bradycardia.
• Nicotinic side effects are also
frequent and include
fasciculations and muscle
cramping, usually less
bothersome than the GI
effects.
CHOLINERGIC CRISIS
• A potential major side effect of
excessive anticholinesterase
medication is weakness, which can
be difficult to distinguish from
worsening MG.
• This paradoxical weakening with
anticholinesterase medications is
called "cholinergic crisis.,“ rarely
seen with dose limitation
of pyridostigmine to ≤120 mg every
three hours, or a total daily dose of
≤960 mg.
• Cholinergic crisis is so rare that it
should not be the presumed cause
of increasing weakness unless the
doses taken are known to
significantly exceed this range.
• Otherwise, even in the presence of
cholinergic side effects, it should be
assumed that the patient's
underlying MG is worsening, and
appropriate treatment should be
initiated.

Side effect management
• Taking pyridostigmine with food can help to reduce bothersome
gastrointestinal side effects.
• Muscarinic side effects can be controlled in many patients with the
use of oral anticholinergic drugs that have little or no effect at the
nicotinic receptors (i.e, do not produce increased weakness).
• These include the following agents:
 Glycopyrrolate 1 mg by mouth
 Propantheline 15 mg by mouth
 Hyoscyamine sulfate 0.125 mg by mouth
• These anticholinergic drugs can be taken prophylactically three
times a day or, alternatively, with each pyridostigmine dose.
• Prominent diarrhea can be reduced by the addition of loperamide
Or diphenoxylate hydrochloride-atropine sulfate with or without
other anticholinergic drugs.

ADDITION OF IMMUNOSUPPRESSIVE
THERAPY

Myasthenia gravis

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Myasthenia gravis

Similar to Myasthenia gravis (20)

Recently uploaded

Recently uploaded (20)

Myasthenia gravis