REFERAT

MYASTHENIA GRAVIS

Disusun oleh :
Aditya Rachmat Febrianto
1102011007
Pembimbing :
Dr. Donny H. Hamid, Sp.S
Kepaniteraan Klinik Neurologi
RSUD. Pasar Rebo
Fakultas Kedokteran Universitas YARSI
Jakarta 2016

1. Definition
Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies
form against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular
junction (NMJ) of the skeletal muscles. The basic pathology is a reduction in the number of
ACh receptors (AChRs) at the postsynaptic muscle membrane brought about by an acquired
autoimmune reaction producing anti-AChR antibodies.
The reduction in the number of AChRs results in a characteristic pattern of progressively
reduced muscle strength with repeated use and recovery of muscle strength after a period of
rest. The ocular and bulbar muscles are affected most commonly and most severely, but most
patients also develop some degree of fluctuating generalized weakness. The most important
aspect of MG in emergency situations is acute worsening of weakness and diagnosis of
myasthenic versus cholinergic crisis and its management.
2. Anatomy
The nerve terminal of the motor nerve enlarges at its end to form the so-called bouton
terminale, or terminal bulb. This bulb lies within a groove or indentation along the muscle
fiber. The presynaptic membrane (on the nerve), postsynaptic membrane (on the muscle
membrane), and the synaptic cleft (the space between the 2 membranes) together constitute
the NMJ. ACh molecules are hydrolyzed by the enzyme acetylcholinesterase (AChE), which
is abundantly present at the NMJ. The surface area of the postsynaptic membrane is increased
by infolding of the membrane adjacent to the nerve terminal. This increase in surface area
enables the NMJ to utilize the ACh fully. AChRs are present in small quantities over most of
the muscle membrane surface but are concentrated heavily at the tips of the NMJs.

Adult AChR comprises 5 subunits (2 alpha, 1 beta, 1 gamma, and 1 delta), each of which
is a membrane-spanning protein molecule. These subunits are homologous across different
species, suggesting that the encoding genes evolved from a common ancestral gene. The

subunits are arranged in a circle, forming a central opening that acts as an ion channel. When
an ACh molecule binds to an AChR, the AChR undergoes a 3-dimensional conformational
change that opens the channel. The presynaptic terminal contains vesicles filled with ACh.
When an action potential travels down a motor nerve and reaches the nerve terminal, the
contents of these vesicles are released into the synaptic cleft in a calcium-dependent manner.
The released ACh molecules diffuse across the synapse and bind to the AChRs at the peaks
of the folds on the postsynaptic membrane.
This binding causes the ion channels in the AChR to open briefly, allowing sodium ions
into the interior of the muscle cell and thereby bringing about partial depolarization of the
postsynaptic membrane and generation of an excitatory postsynaptic potential (EPSP). If the
number of open sodium channels reaches a threshold value, a self-propagating muscle action
potential is generated in the postsynaptic membrane.
3. Epidemiology
MG is uncommon. The estimated annual US incidence is 2 per 1,000,000. The prevalence
of MG in the United States ranges from 0.5 to 14.2 cases per 100,000 people. This figure has
risen over the past 2 decades, primarily because of the increased lifespan of patients with MG
but also because of earlier diagnosis. About 15-20% of patients will experience a myasthenic
crisis. Three fourths of these patients experience their first crisis within 2 years of diagnosis.
In the United Kingdom, the prevalence of MG is 15 cases per 100,000 population. In
Croatia, it is 10 cases per 100,000. In Sardinia, Italy, the prevalence increased from 0.75 per
100,000 in 1958 to 4.5 cases per 100,000 in 1986.
MG can occur at any age. Female incidence peaks in the third decade of life, whereas
male incidence peaks in the sixth or seventh decade. The mean age of onset is 28 years in
females and 42 years in males. Transient neonatal MG occurs in infants of myasthenic
mothers who acquire anti-AChR antibodies via placental transfer of IgG. Some of these
infants may suffer from transient neonatal myasthenia due to effects of these antibodies.
Most infants born to myasthenic mothers possess anti-AChR antibodies at birth, yet only 1020% develop neonatal MG. This may be due to protective effects of alpha-fetoprotein, which
inhibits binding of anti-AChR antibody to AChR. High maternal serum levels of AChR
antibody may increase the chance of neonatal MG; thus, lowering the maternal serum titer
during the antenatal period by means of plasmapheresis may be useful.
Classically, the overall female-to-male ratio has been considered to be 3:2, with a female
predominance in younger adults (ie, patients aged 20-30 years) and a slight male
predominance in older adults (ie, patients older than 50 years). Studies show, however, that
with increased life expectancy, males are coming to be affected at the same rate as females.
Ocular MG shows a male preponderance. The male-to-female ratio in children with MG and
another autoimmune condition is 1:5.
4. Etiology
MG is idiopathic in most patients. Although the main cause behind its development
remains speculative, the end result is a derangement of immune system regulation. MG is

clearly an autoimmune disease in which the specific antibody has been characterized
completely. In as many as 90% of generalized cases, IgG to AChR is present. Even in
patients who do not develop clinical myasthenia, anti-AChR antibodies can sometimes be
demonstrated. Patients who are negative for anti-AChR antibodies may be seropositive for
antibodies against MuSK. Muscle biopsies in these patients show myopathic signs with
prominent mitochondrial abnormalities, as opposed to the neurogenic features and atrophy
frequently found in MG patients positive for anti-AChR. The mitochondrial impairment
could explain the oculobulbar involvement in anti-MuSKpositive MG.
Numerous findings have been associated with MG. For example, females and people with
certain human leukocyte antigen (HLA) types have a genetic predisposition to autoimmune
diseases. The histocompatibility complex profile includes HLA-B8, HLA-DRw3, and HLADQw2 (though these have not been shown to be associated with the strictly ocular form of
MG). Both SLE and RA may be associated with MG. Sensitization to a foreign antigen that
has cross-reactivity with the nicotinic ACh receptor has been proposed as a cause of
myasthenia gravis, but the triggering antigen has not yet been identified.
Various drugs may induce or exacerbate symptoms of MG, including the following:

Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and

ampicillin)
Penicillamine - This can induce true myasthenia, with elevated anti-AChR antibody
titers seen in 90% of cases; however, the weakness is mild, and full recovery is
achieved weeks to months after discontinuance of the drug
Beta-adrenergic receptor blocking agents (eg, propranolol and oxprenolol)
Lithium
Magnesium
Procainamide
Verapamil
Quinidine
Chloroquine
Prednisone
Timolol (ie, a topical beta-blocking agent used for glaucoma)
Anticholinergics (eg, trihexyphenidyl)
Nitrofurantoin has also been linked to the development of ocular MG in 1 case report;
discontinuance of the drug resulted in complete recovery.
Thymic abnormalities are common: Of patients with MG, 75% have thymic disease, 85%
have thymic hyperplasia, and 10-15% have thymoma. Extrathymic tumors may include small
cell lung cancer and Hodgkin disease. Hyperthyroidism is present in 3-8% of patients with
MG and has a particular association with ocular MG.
5. Pathophysiology

With every nerve impulse, the amount of ACh released by the presynaptic motor neuron
normally decreases because of a temporary depletion of the presynaptic ACh stores (a
phenomenon referred to as presynaptic rundown). In MG, there is a reduction in the number
of AChRs available at the muscle endplate and flattening of the postsynaptic folds.
Consequently, even if a normal amount of ACh is released, fewer endplate potentials will be
produced, and they may fall below the threshold value for generation of an action potential.
The end result of this process is inefficient neuromuscular transmission.
Inefficient neuromuscular transmission together with the normally present presynaptic
rundown phenomenon results in a progressive decrease in the amount of muscle fibers being
activated by successive nerve fiber impulses. This explains the fatigability seen in MG
patients. Patients become symptomatic once the number of AChRs is reduced to
approximately 30% of normal. The cholinergic receptors of smooth and cardiac muscle have
a different antigenicity than skeletal muscle and usually are not affected by the disease.
The decrease in the number of postsynaptic AChRs is believed to be due to an
autoimmune process whereby anti-AChR antibodies are produced and block the target
receptors, cause an increase the turnover of the receptors, and damage the postsynaptic
membrane in a complement-mediated manner. Clinical observations support the idea that
immunogenic mechanisms play important roles in the pathophysiology of MG. Such
observations include the presence of associated autoimmune disorders (eg, autoimmune
thyroiditis, systemic lupus erythematosus [SLE], and rheumatoid arthritis [RA]) in patients
with MG.
Moreover, infants born to myasthenic mothers can develop a transient myasthenialike
syndrome. Patients with MG will have a therapeutic response to various immunomodulating
therapies, including plasmapheresis, corticosteroids, intravenous immunoglobulin (IVIg),
other immunosuppressants, and thymectomy.
The exact mechanism of loss of immunologic tolerance to AChR, a self-antigen, is not
understood. MG can be considered a B cellmediated disease, in that it derives from
antibodies (a B cell product) against AChR. However, the importance of T cells in the
pathogenesis of MG is becoming increasingly apparent. The thymus is the central organ in T
cellmediated immunity, and thymic abnormalities such as thymic hyperplasia or thymoma
are well recognized in myasthenic patients.
Patients without anti-AChR antibodies are recognized as having seronegative MG
(SNMG). Many patients with SNMG have antibodies against muscle-specific kinase
(MuSK). MuSK plays a critical role in postsynaptic differentiation and clustering of AChRs.
Patients with anti-MuSK antibodies are predominantly female, and respiratory and bulbar
muscles are frequently involved. Another group has reported patients who exhibit prominent
neck, shoulder, and respiratory weakness.
The role of the thymus in the pathogenesis of MG is not entirely clear, but 75% of
patients with MG have some degree of thymus abnormality (eg, hyperplasia or thymoma).
Histopathologic studies have shown prominent germinal centers. Epithelial myoid cells
normally present in the thymus do resemble skeletal muscle cells and possess AChRs on their

surface membrane. These cells may become antigenic and unleash an autoimmune attack on
the muscular endplate AChRs by molecular mimicry.
The question of why MG afflicts the extraocular muscles first and predominantly remains
unanswered. The answer probably has to do with the physiology and antigenicity of the
muscles in question.
6. Presentation
Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs
during the course of illness in 90%. Bulbar muscle weakness is also common, along with
weakness of head extension and flexion. Weakness may involve limb musculature with a
myopathylike proximal weakness that is greater than the distal muscle weakness. Isolated
limb muscle weakness as the presenting symptom is rare and occurs in fewer than 10% of
patients. In a surveillance study of 57 cases of pediatric myasthenia, including 34 generalized
and 18 ocular cases of juvenile myasthenia gravis (JMG) and 5 cases of congenital
myasthenic syndrome, ptosis was the most common symptom, occurring in all patients with
ocular JMG and 82% of those with generalized JMG. Tests for acetylcholine receptor
antibodies were positive in 67% of the patients with generalized JMG and 44% of those with
ocular. All 33 patients with JMG who were treated with pyridostigmine showed
improvement, and the majority of patients treated with steroids or intravenous
immunoglobulin also improved. Of the 17 patients with ocular JMG treated with
pyridostigmine, 88% improved.
Patients progress from mild to more severe disease over weeks to months. Weakness
tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb
muscles. On the other hand, symptoms may remain limited to the extraocular and eyelid
muscles for years. Rarely, patients with severe, generalized weakness may not have
associated ocular muscle weakness.
The disease remains exclusively ocular in only 16% of patients. About 87% of patients
have generalized disease within 13 months after onset. In patients with generalized disease,
the interval from onset to maximal weakness is less than 36 months in 83% of patients.
Anti-MuSK-positive MG has several clinical characterisitics that differ from more
common anti-ACh-R-positive myasthenia gravis. It occurs predominately in women with
onset typically occurring in the fourth decade of life. Patients with anti-MuSK antibodies
rarely have isolated occular presentation but may have significant oculobulbar involvelment
and respiratory muscle weakness and may have facial and tongue muscle atrophy.
Myasthenic crisis is also more common
Exposure to bright sunlight, surgery, immunization, emotional stress, menstruation, and
physical factors might trigger or worsen exacerbations. Intercurrent illness (eg, viral
infection) or medication can exacerbate weakness, quickly precipitating a myasthenic crisis
and rapid respiratory compromise. Spontaneous remissions are rare. Long and complete
remissions are even less common. Most remissions with treatment occur during the first 3
years of disease.

In May 1997, the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis
Foundation of America (MGFA) formed a task force to address the need for universally
accepted classifications, grading systems, and analytic methods for management of patients
undergoing therapy and for use in therapeutic research trials. As a result, the MGFA Clinical
Classification was created.[3] This classification divides MG into 5 main classes and several
subclasses, as follows.

Class I MG is characterized by the following:

Any ocular muscle weakness
May have weakness of eye closure
All other muscle strength is normal

Class II MG is characterized by the following:

Mild weakness affecting other than ocular muscles
May also have ocular muscle weakness of any severity

Class IIa MG is characterized by the following:

Predominantly affecting limb, axial muscles, or both
May also have lesser involvement of oropharyngeal muscles

Class IIb MG is characterized by the following:

Predominantly affecting oropharyngeal, respiratory muscles, or both
May also have lesser or equal involvement of limb, axial muscles, or both

Class III MG is characterized by the following:

Moderate weakness affecting other than ocular muscles
May also have ocular muscle weakness of any severity

Class IIIa MG is characterized by the following:

Predominantly affecting limb, axial muscles, or both
May also have lesser involvement of oropharyngeal muscles

Class IIIb MG is characterized by the following:

Predominantly affecting oropharyngeal, respiratory muscles, or both
May also have lesser or equal involvement of limb, axial muscles, or both

Class IV MG is characterized by the following:

Severe weakness affecting other than ocular muscles
May also have ocular muscle weakness of any severity

Class IVa MG is characterized by the following:

Predominantly affecting limb, axial muscles, or both
May also have lesser involvement of oropharyngeal muscles

Class IVb MG is characterized by the following:

Predominantly affecting oropharyngeal, respiratory muscles, or both
May also have lesser or equal involvement of limb, axial muscles, or both

Class V MG is characterized by the following:

Defined by intubation, with or without mechanical ventilation, except when used during
routine postoperative management
Use of a feeding tube without intubation places the patient in class IVb

7. Physical Examination
Patients with MG can present with a wide range of signs and symptoms, depending on
the severity of the disease. Mild presentations may be associated with only subtle findings,
such as ptosis, that are limited to bulbar muscles. Findings may not be apparent unless
muscle weakness is provoked by repetitive or sustained use of the muscles involved.
Recovery of strength is seen after a period of rest or with application of ice to the affected
muscle. Conversely, increased ambient or core temperature may worsen muscle weakness.
Variability in weakness can be significant, and clearly demonstrable findings may be
absent during examination. This may result in misdiagnosis (eg, functional disorder). The
physician must determine strength carefully in various muscles and muscle groups to
document severity and extent of the disease and to monitor the benefit of treatment. Another
important aspect of the physical examination is to recognize a patient in whom imminent
respiratory failure is imminent. Difficulty breathing necessitates urgent or emergent
evaluation and treatment.
Weakness can be present in a variety of different muscles and is usually proximal and
symmetric. Sensory examination and deep tendon reflexes are normal. Weakness of the facial
muscles is almost always present. Bilateral facial muscle weakness produces a masklike face
with ptosis and a horizontal smile. The eyebrows are furrowed to compensate for ptosis, and
the sclerae below the limbi may be exposed secondary to weak lower lids. Mild proptosis
attributable to extraocular muscle weakness also may be present.
Weakness of palatal muscles can result in a nasal twang to the voice and nasal
regurgitation of food (especially liquids). Chewing may become difficult. Severe jaw
weakness may cause the jaw to hang open (the patient may sit with a hand on the chin for
support). Swallowing may become difficult, and aspiration may occur with fluids, giving rise
to coughing or choking while drinking. Weakness of neck muscles is common, and neck
flexors are usually affected more severely than neck extensors are.
Certain limb muscles are involved more commonly than others (eg, upper limb muscles
are more likely to be involved than lower limb muscles). In the upper limbs, deltoids and
extensors of the wrist and fingers are affected most. The triceps is more likely to be affected
than the biceps. In the lower extremities, commonly involved muscles include hip flexors,
quadriceps, and hamstrings, with involvement of foot dorsiflexors or plantar flexors less
common.

Respiratory muscle weakness that produces acute respiratory failure is a true

neuromuscular emergency, and immediate intubation may be necessary. Weakness of the
intercostal muscles and the diaphragm may result in carbon dioxide retention as a result of
hypoventilation. Respiratory failure usually occurs around the time of surgery (eg, after
thymectomy) or during later stages of the disease. However, it can be a presenting feature in
about 14-18% of patients with MG.[24]
Weak pharyngeal muscles may collapse the upper airway. Careful monitoring of
respiratory status is necessary in the acute phase of MG. Negative inspiratory force, vital
capacity, and tidal volume must be monitored carefully. Relying on pulse oximetry to
monitor respiratory status can be dangerous. During the initial phase of neuromuscular
hypoventilation, carbon dioxide is retained but arterial blood oxygenation is maintained. This
can lull the physician into a false sense of security regarding a patients respiratory status.
Typically, extraocular muscle weakness is asymmetric. The weakness usually affects
more than 1 extraocular muscle and is not limited to muscles innervated by a single cranial
nerve; this is an important diagnostic clue. The weakness of lateral and medial recti may
produce a pseudointernuclear ophthalmoplegia, described as limited adduction of 1 eye, with
nystagmus of the abducting eye on attempted lateral gaze. The nystagmus becomes coarser
on sustained lateral gaze as the medial rectus of the abducting eye fatigues.
Eyelid weakness results in ptosis. Patients may furrow their foreheads, using the frontalis
muscle to compensate for this weakness. A sustained upward gaze exacerbates the ptosis;
closing the eyes for a short period alleviates it.

8. Diagnosis
In patients who present with a changeable, specifically fatigable, diplopia or ptosis and
the typical myasthenic facies-unequally drooping eyelids, relatively immobile mouth turned
down at the corners, a smile that looks more like a snarl, a hanging jaw supported by the
hand- the diagnosis can hardly be overlooked. However, only a few patients display this fully
developed syndrome. Ptosis, diplopia, difficulty in speaking or swallowing, or weakness of
the limbs is at first mild and inconstant and may mistaken for a cerebrovascular disease.
however, the finding that sustained activity of small cranial muscles results in weakness (e.g
increasing droop of eyelids while looking at the ceiling or diplopia when fixating in lateral or
vertical gaze or reading for 2 to 3 min) and that contraction improves after a brief rest is
virtually diagnostic, even in early stages of the disease. Any other affected group of muscles
may be tasted in similar fashion. The characteristic ocular signs have already been described.
For confirmation, the measurement of specific antiobody (anti-AChR), electromyography,
and certain pharmacologic test described below are necessary. Several special clinical
problems and associated conditions are summarized further on.
Electrophysiologic Testing. Caracteristic of myasthernia is a rapid reduction in the
amplitude of compound muscle action potentials during a series of repetititive stimulation of
a peripheral nerve at a rate of 3 per second. reversal of this response by neostigmine or

edrophonium has been a reliable confirmatory finding in most cases. A decremental response
to stimulation can usually be obtained most often from proximal limb muscles followed by
the facial and, to a lesser extent, the hand muscles, which may or may not be clinically weak.
During corticosteroid therapy, a slight initial incrementing response after voluntary
contraction that characterizes the lambert-Eaton syndrome (see further on).
Single-Fiber Electromyography (EMG) represents an even more sensitive method of
detecting the defect in neuromuscular transmission. This technique demonstrates an
inconstancy of the normally invariant interval between the firing of muscle fibers connected
to the same motor unit (Jitter-see Single-Fiber Electromyography in chap. 45) or
complete blocking of successive discharges from single muscle fibers belonging to the same
motor unit. The test requires a great deal of coopration from the patient and that contraction
of a musclr br sustained at just the right amplitude in order to isolate single muscle fibers
from the same unit. It is also possible to detect such pairs of fiber by electrical stimulation of
a nerve. Nerve conduction velocities and distal motor latencies are normal unless there is a
coincident polyneuropathy.
Neostigmine Test Almost as valuable as electrophysiologic testing is testing with the
antocholinesterase inhibitors neostigmine and in the past, edrophorium a more rapidly acting
agent. These drugs prolong and exaggerante the effects of Ach in the synapse and thereby
produce an increment in muscle power in the patient with myasthernia. Edrophorium is not
easily available in the united states at the time of this writing but neostigmine affords a
longer time for observation, as noted in the next paragraph. The test are performed in the
following manner. After the estimation of strength in a cranial (usually the levator palpebrae
or an extra ocular muscle) or limb muscle (by dynamometry), or vital capacity, neostigmine
is injected intramuscularly in a dose of 1.5 mg, atropine sulfate (0,8 mg) should be given
several minutes in advance to counteract the unpleasant muscarinic effect of neostigmine
(salivation, sweating, broncorrea, borborygmi, bowel cramps and sometimes diarrhea).
Neostigmine may alternatively be given intravenously in a dose of 0,5mg but its effect is
often too brief to be as useful. After intramuscular injection of neostigmine, objective
improvement occurs within 10 to 15 min, reaches its peak at 20 min, and last up to 1 h,
allowing for careful verification of the neurologic improvement. Many neurologist perform
this test twice, once eith an injection of saline as a control.
Alternatively, 1 mg (0,1mL) of endrophonium is given intravenously; if this dose is
tolerated and no definite improvement in strength occurs after 45s, another 4 to 9 mg is
injected. A total doseof 10mg is rarely necessary. Most patients who respond do so after 3 to
5 mg has been administrated. The mild muscarinic effects of edorphorium are blocked by
pretreatment with atropine 0,8 mg subcutaneously as for neostigmine. The clinical effect of
improved ptosis, extraocular movements, oropharingeal function, arm and shoulder
abduction, or vital capacity persists for no more than 5 min with edrophorium and 60 mins
with neostigmine.
One caution: with either drug, some patients deteriorate immediately, but briefly, as a
result of an increase in rpulmonary secretion. A positive test consist of visible (objective)

improvement in muscle contractility, fusion of diplopia, or resolution fatigable ptosis.

Dynamometry and measurement of forced vital capacity serve as more objective markers of
improvement, or lack of effect. The report of subjective improvement alone is not dependable
and one must be distrustful of equivocal test results, which may occur with ocular palsies due
to tumors, tyroid disease, Guillain-Barre syndromes (GBS), progressive supranuclear palsy,
or carotid aneurisms (pseudooccular myasternia)
A negative test with an anticholinesterase agent does not entirely exclude myasternia
gravis but is a strong point against the diagnosis. In a small number of patients with periodic
and purely ocular symptoms who later prove to have myasternia gravis, the edrophorium and
neostigmine test (and electropysiologic studies and AChR antibody measuremens) may be
entirely normal during the first or even sfter several acute episodes. Only later, for even after
several acut episodes. Only lster, for inexplicable reasons, do these test become positive.
Finslly, the anticolinesterase-inhibiting drugs carry a small risk of inducing ventriculsr
fibrillation and cardiac arrest do that testing should be carried out where emergency support
is accessible.
Measurement of Receptor Antibodies in Blood the detection of anti-AChR sntibodies
provides a reasonably sensitive and highly specific test for the diagnosis of myasthernia. The
radioimmunoassay method of detection isaccurate and widely used. Serum antibodies are
found in 80 to 90 percent of patients with generalized myasthernia gravis and in
approximately 60 percent of those whose symptoms are restricted to the ocular muscles
(Vincent snd newsome-davis). For the most part, adults with myasternia whose sera are
persistently negative for AChR antibodies do not differ clinically or electromyographicly
from those with antibodies with the exception noted below. Persistently negative AChR
antibody tests are more frequently found in patients with generalized weakness. Patients with
a tymoma and severe generalized myasternia are practically always seropositive,
interestingly, the antibody tieters usually remain elevated during clinical remissions.
Other diagnostic test performed routinely in essentialy all patients with myasthernia
gravis include CT of the chest (for the detection of thumic enlargement or tymoma), test of
tyroid function for reasons discussed further on, and in cases of uncertain diagnosis,
magnetic resonance imaging ot the cranium and orbits to exclude compressive and
inflammatory lesion of the cranial nerves and ocular muscles.
9. Treatment
The treatment of this disease involves the careful use of two groups of druganticholinesterases and immunosuppresants including corticosteroids and in special acute
sircumstances, plasma exchange and inravenous immunoglobulin, an elective thymectomy is
appropriate in many patients as discussed below
Anticolinesterase Drugs. The two drugs that give the best results in ameliorating
myasthernia weakness are neostigmine (Prostigmine) and Pyridostigmine (Mestinon), the
latter being preferred by most clinicians and patients. The usual dose of pyridostigmine is 30
to 90 mg given every 6 h (typically a 60 mg pill is tried first); the oral dose of neostigmine

ranges from 7.5 to 45mg given every 2 to 6 h. extended-action forms of both drugs are
available but are given at bedtime mainly to patients who complain of weakness during the
night or early morning hours. The dosage of these drug and their frequency of administration
vary considerably from patient to patient, but we agree with Drachman (2003) that the
maximal useful dosage of pyridostigmine rarely exceeds 120 mg given every 3 h. table 49-1
lists the approximate dose-equivalents of these various drugs.
Corticosteroids. For the patient with moderate to severe generalized weakness who is
responding inadequately to anticholinesterase drugs, the long term administration of
corticosteroid is the most consistently effective from of treatment, as described in a large
series of patients by pascuzzi and colleagues. Small doses of corticosteroids (prednisone 15
to 25 mg daily) alone or in combination with azathioprine are also often adequate to control
ocular myasternia. However, one must be prepared to contend with the side effects of long
term corticosteroid therapy and we hesitate to undertake such a program in children or
patients with severe diabetes or other disease that are likely tobe aggravated. Because recent
experience with the newer immunosuppressive agents was not incorporated into most prior
series, the uniform use of steroids might not be correct
The usual form of corticosteroid therapy is prednisone (or corresponding doses of
prednisone), beginning with 15 to 20 mg/d and increasing the dose gradually until a
statisfactory clinical response is obtained or until a daily dose of 50 to 60 mg is reached.
Once the maximal effect from prednisone has been attained, the dosage can be reduced
gradually over month to the lowest point at which it is still effective.
Azathioprine and Other Immunosuppresive Drugs. Azathioprine is a useful adjunct to
steroids in patients who cannot tolerate or fail to respond to pednisone. Treatment typically
begins with 50 mg ( 1 tablet) bid for few days; if this is tolerated, the dosage is raised to 2 to
3 mg/kgBB/d (150 to 250 mg daily). Liver function tetst and blood cell count should be
checked regularly.
Cyclosporine is another immunosuppressive drug that has shown benefit in clinical trials
(Tindall et al). it is given in 2 divided doses daily, to total of 6 mg/Kg, but not often used
currently because of serious side effects (hypertention, nephrotoxicity) and its high cost.
Because of the success of alternative regimens, we have had occasion over the years to use
cyclosporine only once for myasthernia.
Mycophenolate is currently being used as an adjunct to corticosteroids and has been
beneficial in several small terials but faild to demonstrate similar effect in larger controlled
studies
Plasma Exchange and Intervenous Immune Globuline. For severe myasthernia that is
refractory to treatment with anticolinesterase drug and prednisone, or during an acute period
of worsening, one must resort to other measures. Striking temporary remissins ( 2 to 8
weeks) may be obtained by the use of plasma exchange. This form of treatment may
belifesaving during a myasthenic crisis. The number and volume of exchanges required in
these circumstances is somewhat arbitrary but they tend to be less than those required for
GBS; several exchanges fo 2 to 3,5 L each (totaling approximately 125 mL/kg)

Intravenous immune globulin is similary useful in the short-term control of acutely

worsening myasthernia. The usual dose is 2 g/kg given in divided doses over 3 to 5 days.
Tymectomy. This opration, first introduced by blalock, despite the absence of proofin
trials, is considered an appropriate procedure for many patients with generalized myasthernia
gravis between puberty and 55 years of age. The surgery is performed electively and not
during an acute deterioration of myasthernia. The remission rate after thymectomy is
approximately 35 percent provided that the procedure is done in the first year or two after
onset of the disease, and another 50 percent will improve to some extent (Buckingham et al).
A suprasternal approach for removal of the gland has been developed and results in less
postoperative pain and morbidity than occurs with a transsternal thoracotomy but the
transsternal operation may be preferable because it assures a more complete removal of
thymic tissue. Thymectomy is best performed in a hospital where there is close collaboration
between the thoracic surgeon and the neurologist. If the patient is weak preoperatively, a
course of plasma exchange or immune globulin may be given preceding the surgical
procedure. Large :stress doses of corticosteroids seem to be unnecessary in most patient
who have been takig these medications chronically. Neostigmine intramuscullary, may be
given every 3 to 6 h postoperative. Thymectomy may also be safe and effective treatment in
eldery patients with myasthernia.
Despite this endorsement of thymectomy for generalized myasthernia, it has remained an
unproven therapy by a modern trial and attempts to recruit patients for such an endeavor have
been difficult.