REFERENCE

MYASTHENIA GRAVIS

Ika Wulan Permata

1102012118

Counsellor :
dr. Donny H Hamid, Sp.S

FACULTY OF MEDICINE YARSI UNIVERSITY

CLINICAL CLERKSHIP DEPARTEMENT OF NEUROLOGY
PASAR REBO REGIONAL GENERAL HOSPITAL
 CONTENTS

Contents ........................................................................................................................... 1
Chapter I............................................................................................................................ 2
Introduction......................................................................................................... 2
Chapter II .......................................................................................................................... 3
2.1 Anatomy ....................................................................................................... 3
2.2 Definition ...................................................................................................... 4
2.3 Etiology......................................................................................................... 4
2.4 Epidemiology................................................................................................ 6
2.5 Pathophysiology ........................................................................................... 7
2.6 Clinical manifestation ................................................................................... 8
2.7 Diagnosis .................................................................................................... 11
2.8 Differential diagnosis.................................................................................. 17
2.9 Treatment .................................................................................................... 19
2.10 Complication............................................................................................. 23
2.10 Prognosis ................................................................................................... 23
References ....................................................................................................................... 24

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 CHAPTER I
INTRODUCTION

Myasthenia Gravis (pronounced My-as-theen-ee-a Grav-us) comes from the Greek and Latin
words meaning "grave muscular weakness." The most common form of MG is a chronic
autoimmune neuromuscular disorder that is characterized by fluctuating weakness of the voluntary
muscle groups. The prevalence of MG in the United States is estimated to be about 20/100,000
population. However, MG is probably under diagnosed and the prevalence may be higher.
Myasthenia Gravis occurs in all races, both genders, and at any age. MG is not thought to be
directly inherited nor is it contagious. It does occasionally occur in more than one member of the
same family.

The voluntary muscles of the entire body are controlled by nerve impulses that arise in the brain.
These nerve impulses travel down the nerves to the place where the nerves meet the muscle fibers.
Nerve fibers do not actually connect with muscle fibers. There is a space between the nerve ending
and muscle fiber; this space is called the neuromuscular junction. When the nerve impulse
originating in the brain arrives at the nerve ending, it releases a chemical called acetylcholine.
Acetylcholine travels across the space to the muscle fiber side of the neuromuscular junction where
it attaches to many receptor sites. The muscle contracts when enough of the receptor sites have
been activated by the acetylcholine. In MG, there can be as much as an 80% reduction in the
number of these receptor sites. The reduction in the number of receptor sites is caused by an
antibody that destroys or blocks the receptor site. Antibodies are proteins that play an important
role in the immune system. They are normally directed at foreign proteins called antigens that
attack the body. Such foreign proteins include bacteria and viruses. Antibodies help the body to
protect itself from these foreign proteins. For reasons not well understood, the immune system of
the person with MG makes antibodies against the receptor sites of the neuromuscular junction.
Abnormal antibodies can be measured in the blood of many people with MG. The antibodies
destroy the receptor sites more rapidly than the body can replace them. Muscle weakness occurs
when acetylcholine cannot activate enough receptor sites at the neuromuscular junction.

Myasthenia Gravis (MG as we know it) is not the only medical condition that is referred to as MG.
There was a web posting about a venereal infection caused by a bacteria Mycoplasma genitalium
that is also sometimes abbreviated as MG. Myasthenia Gravis has nothing to do with Mycoplasma
genitalium. Please do not be confused if you run across an article about MG being sexually
transmitted. Myasthenia gravis is not transmitted from one person to another by intimate contact
or any form of contact.

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 CHAPTER II
2.1 Anatomy
In MG, autoantibodies (immunoglobulin G [IgG]) develop against ACh nicotinic
postsynaptic receptors at the NMJ of skeletal muscles.[1,2] The reasons for this development are
unknown, although it is clear that certain genotypes are more susceptible.[11] To understand MG,
it is necessary to be familiar with the normal anatomy and functioning of the NMJ.
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 (see the image
below).

Normal neuromuscular junction showing a presynaptic terminal with a motor nerve ending in an enlargement (bouton terminale):
Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.

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 (see the image below).

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When an ACh molecule binds to an AChR, the AChR undergoes a 3-dimensional conformational change that opens
the channel. Acetylcholine receptor. Note 5 subunits, each with 4 membrane-spanning domains forming a rosette with
a central opening. The central opening acts as an ion 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.

2.2 Definition
Myasthenia gravis (MG) is an acquired autoimmune disorder characterized by fatigable and
fluctuating muscle weakness preferentially affecting certain muscle groups. In most cases it results
from serum antibodies targeting the acetylcholine receptors (AChR) on the postsynap- tic
membrane of the neuromuscular junction (NMJ). Treatment of MG consists of symptomatic
control with cholinesterase inhibitors (CIs) and immunotherapies.
Myasthenia gravis is a disorder of neuromuscular transmission characterised by:
Weakness and fatiguing of some or all muscle groups.
Weakness worsening on sustained or repeated exertion, or towards the end of the day, relieved
by rest.
This condition is a consequence of an autoimmune destruction of the NICOTINIC
POSTSYNAPTIC RECEPTORS FOR ACETYLCHOLINE.

2.3 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
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as 90% of generalized cases, IgG to AChR is present.[14] 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-MuSK (Muscle specific Kinase)positive MG.[15]

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 HLA-DQw2 (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)
Neuromuscular blocking agents (eg, vecuronium and curare) - These should be used
cautiously in myasthenic patients to avoid prolonged neuromuscular blockade
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

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 small cell lung cancer and Hodgkin disease. [16, 17] Hyperthyroidism is present in 3-8%
of patients with MG and has a particular association with ocular MG.

2.4 Epidemiology
United States statistics
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. [6] About 15-20% of patients will experience a myasthenic crisis.
Three fourths of these patients experience their first crisis within 2 years of diagnosis.[11]

International statistics
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.

Age-related demographics
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 3neonatal 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 10-20%
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.

Sex-related demographics
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). [6, 10] 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.

Race-related demographics
The onset of MG at a young age is slightly more common in Asians than in other races.[6]

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2.5 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.

Anti-AChR antibody is found in approximately 80-90% of patients with MG. Experimental

observations supporting an autoimmune etiology of MG include the following:

Induction of a myasthenialike syndrome in mice by injecting a large quantity of immunoglobulin

G (IgG) from MG patients (ie, passive transfer experiments)
Demonstration of IgG and complement at the postsynaptic membrane in patients with MG

Induction of a myasthenialike syndrome in rabbits immunized against AChR by injecting them

with AChR isolated from Torpedo californica (the Pacific electric ray)

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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.

Antibody response in MG is polyclonal. In an individual patient, antibodies are composed of

different subclasses of IgG. In most instances, 1 antibody is directed against the main
immunogenic region (MIR) on the alpha subunit. The alpha subunit is also the site of ACh binding,
though the binding site for ACh is not the same as the MIR. Binding of AChR antibodies to AChR
results in impairment of neuromuscular transmission in several ways, including the following:

Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and
degradation of AChR molecules
Causing complement-mediated destruction of junctional folds of the postsynaptic membrane
Blocking the binding of ACh to AChR

Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic
membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs

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. [12, 13]

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.

2.6 Clinical Manifestation

Signs and symptoms
Up to 90% of patients present in early adult life (<40 years of age). Female:male ratio 2:1. The
disorder may be selective, involving specific groups of muscles.

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Several clinical subdivisions are recognised:
Class 1 ocular muscles only 20%
Class 2 Mild generalised weakness
Class 3 Moderate generalised and mild to moderate ocular-bulbar weakness
Class 4 Severe generalised and ocular-bulbar weakness
Class 5 Myasthenic crises
Approximately 40% of class I will eventually become widespread. The rest remain purely ocular
throughout the illness.
Respiratory muscle involvement accompanies severe illness.

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The presentation of MG has the following characteristics:

The usual initial complaint is a specific muscle weakness rather than generalized weakness
Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs
during the course of illness in 90%
The disease remains exclusively ocular in only 16% of patients
Rarely, patients have generalized weakness without ocular muscle weakness
Bulbar muscle weakness is also common, along with weakness of head extension and
flexion
Limb weakness may be more severe proximally than distally
Isolated limb muscle weakness is the presenting symp6tom in fewer than 10% of patients
Weakness is typically least severe in the morning and worsens as the day progresses
Weakness is increased by exertion and alleviated by rest
Weakness progresses from mild to more severe over weeks or months, with exacerbations
and remissions
Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal
and limb muscles. About 87% of patients have generalized disease within 13 months after
onset
Less often, symptoms may remain limited to the extraocular and eyelid muscles for years
The following factors may trigger or worsen exacerbations:

Bright sunlight
Surgery
Immunization
Emotional stress
Menstruation
Intercurrent illness (eg, viral infection)
Medication (eg;aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin,
beta-blockers, procainamide, statins)

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The Myasthenia Gravis Foundation of America Clinical Classification divides MG into 5 main
classes and several subclasses [3] :

Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle
strength is normal
Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle
weakness of any severity
Class IIa: Predominantly affecting limb, axial muscles, or both; may also have lesser
involvement of oropharyngeal muscles
Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also
have lesser or equal involvement of limb, axial muscles, or both
Class III: Moderate weakness affecting other than ocular muscles; may also have ocular
muscle weakness of any severity
Class IIIa: Predominantly affecting limb, axial muscles, or both; may also have lesser
involvement of oropharyngeal muscles
Class IIIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also
have lesser or equal involvement of limb, axial muscles, or both
Class IV: Severe weakness affecting other than ocular muscles; may also have ocular
muscle weakness of any severity
Class IVa: Predominantly affecting limb, axial muscles, or both; may also have lesser
involvement of oropharyngeal muscles
Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also
have lesser or equal involvement of limb, axial muscles, or both; use of a feeding tube
without intubation
Class V: Defined by the need for intubation, with or without mechanical ventilation, except
when used during routine postoperative management.

2.7 Diagnosis
History

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. [19, 20] All 33 patients with JMG who were
treated with pyridostigmine showed improvement, and the majority of patients treated with

11
steroids or intravenous immunoglobulin also improved. Of the 17 patients with ocular JMG treated
with pyridostigmine, 88% improved. [20] 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. [21] 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. [22] Myasthenic crisis is also more common. [23]

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.

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.

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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.

Evidence of coexisting autoimmune diseases

MG is an autoimmune disorder, and other autoimmune diseases are known to occur more
frequently in patients with MG than in the general population. Some autoimmune diseases that

13
occur at higher frequency in MG patients are hyperthyroidism, rheumatoid arthritis, scleroderma,
and lupus.

A thorough skin and joint examination may help diagnose any of these coexisting diseases.
Tachycardia or exophthalmos point to possible hyperthyroidism, which may be present in up to
10-15% of patients with MG. This is important because in patients with hyperthyroidism,
weakness may not improve if only the MG is treated.

Laboratory

The antiacetylcholine receptor (AChR) antibody (Ab) test is reliable for diagnosing autoimmune
myasthenia gravis (MG). It is highly specific (as high as 100%, according to Padua et al). [4]
Results are positive in as many as 90% of patients who have generalized MG but in only 50-70%
of those who have only ocular MG; thus false negatives are common in cases of purely ocular MG.

False-positive anti-AChR Ab test results have been reported in cases of thymoma without MG and
in patients with Lambert-Eaton myasthenic syndrome, small cell lung cancer, or rheumatoid
arthritis treated with penicillamine, as well as in 1-3% of the population older than 70 years.

Tindall reported AChR Ab results and mean Ab titers in a group of patients with MG [25]

Table. Prevalence and Titers of Antibody to Acetylcholine Receptor in Patients with Myasthenia
Gravis

*Osserman classification: R = remission, I = ocular only, IIA = mild generalized, IIB = moderate
generalized, III = acute severe, IV = chronic severe.

These data suggest a trend toward higher Ab titers in more severe disease, though the titer does
not predict severity in an individual patient. Changes in the anti-AChR titer correlate with long-
term improvement induced by prednisone or azathioprine; the same changes are not observed
consistently in patients who undergo thymectomy. However, this finding is not consistent, and

14
serial Ab titers alone are not reliable. Accordingly, serial Ab titers by themselves are not clinically
useful for judging a patients response.

Antistriated muscle antibody

The antistriated muscle (anti-SM) Ab test is also important in patients with MG. Anti-SM Ab is
present in about 84% of patients with thymoma who are younger than 40 years and less often in
those without thymoma. Thus, a positive test result should prompt a search for thymoma in patients
younger than 40 years. In individuals older than 40 years, anti-SM Ab can be present without
thymoma.

Anti-MuSK antibody

About half of the patients with negative results for anti-AChR Ab (seronegative MG) may have
positive test results for antibody to muscle-specific kinase (MuSK), a receptor tyrosine kinase that
is essential for neuromuscular junction development. [26] These patients may represent a distinct
group of autoimmune MG, in that they show some collective characteristics that are different from
those of anti-AChRpositive patients. [27]

Anti-MuSKpositive individuals tend to have more pronounced bulbar weakness and may have
tongue and facial atrophy. They may have neck, shoulder and respiratory involvement without
ocular weakness. They are also less likely to respond to acetylcholine esterase (AChE) inhibitors,
and their symptoms may actually worsen with these medications. [28, 29]

Anti-lipoprotein-related protein 4 (LRP4) antibody

Lipoprotein-related protein 4 is present on the postsynaptic membrane and is a receptor for agrin
and is essential for neuromuscular junction formation. Antobody to this protein is present in 2-
27% of double seronegative myasthenics (absence of AChR and Anti-MuSK antobodies) [30] .

Antistriational antibody

Serum from some patients with MG possesses antibodies that bind in a cross-striational pattern to
skeletal and heart muscle tissue sections. These antibodies react with epitopes on the muscle
protein titin and ryanodine receptors (RyR).

Almost all patients with thymoma and MG, as well as half of the late-onset MG patients (onset at
50 years or later), manifest a broad striational antibody response. Striational antibodies are rarely
found in anti-AChRnegative patients. They can be used as prognostic determinants in MG; as in
all subgroups of MG, higher antibody titers are associated with more severe disease. [31] Because
of a frequent association with thymoma, the presence of titin/RyR antibodies should arouse a
strong suspicion of thymoma in a young patient with MG.

15
Other laboratory studies

Testing for rheumatoid factor and antinuclear antibodies (ANAs) is indicated to rule out systemic
lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Thyroid function tests are indicated to rule out associated Graves disease or hyperthyroidism. This
is essential, especially in patients with ocular MG where the concomitant hyperthyroidism is most
frequent.

Radiography, CT, and MRI

On plain anteroposterior and lateral views, radiography may identify a thymoma as an anterior
mediastinal mass. A negative chest radiograph does not rule out a smaller thymoma, in which case
a chest computed tomography (CT) scan is required. Chest CT scan should be obtained to identify
or rule out thymoma or thymic enlargement in all cases of MG (see the images below). This is
especially true in older individuals.

CT-Scan of chest and mediastinum showing thymoma in patients with Myasthenia Gravis

CT scan of chest showing an anterior mediastinal mass (thymoma) in a patient with myasthenia gravis.

It is essential to rule out mass lesions compressing the cranial nerves in strictly ocular MG. CT or
preferably magnetic resonance imaging (MRI) of the brain and orbit is indicated. It is helpful when
the diagnosis of MG is not established and to rule out other causes of cranial nerve deficits. MRI
can evaluate for intraorbital or intracranial lesions, basal meningeal pathology, or multiple
sclerosis.

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Electrodiagnostic Studies

Electrodiagnostic studies can demonstrate a defect of neuromuscular transmission. The following

2 studies are commonly performed:

Repetitive stimulation of a muscle at 2-3 Hz, also known as repetitive nerve stimulation (RNS)

Single-fiber electromyography (SFEMG), aimed at evaluating neuromuscular block, jitter, and

fiber density

SFEMG is more sensitive than RNS in assessing MG. However, SFEMG is technically more
difficult and much more dependent on the experience and skill of the testing physician.
Consequently, RNS is the most frequently performed neurophysiologic test of neuromuscular
transmission.

Repetitive nerve stimulation

During low-frequency (1-5 Hz) RNS, the locally available acetylcholine (ACh) becomes depleted
at all neuromuscular junctions (NMJs), and less is therefore available for immediate release. This
results in smaller excitatory postsynaptic potentials (EPSPs).

In patients without MG, all EPSPs exceed the threshold to generate an action potential (ie, there is
a safety factor). No change in the summated compound muscle action potential (CMAP) is noted.
In patients with MG, the number of AChRs is reduced, lowering the safety factor. During RNS,
some EPSPs may not reach threshold, which means that no action potential is generated. This
results in the decrement in the amplitude of the CMAP.

In patients with myasthenia gravis, this decremental response usually has a maximum decrement
at the fourth or fifth response, followed by a tendency toward repair (see the image below). A
stimulation rate of 1-5 per second should result in a 10% or more decrease in amplitude by the
fourth or fifth action potential; any decrement over 10% is considered abnormal. The most
common employed stimulation rate is 3 Hz.

2.8 Differetial diagnosis

Ocular MG

Thyroid ophthalmopathy:

Typical symptoms: proptosis, lid retraction, lid lag. Ptosis is usually not present.

MG and Graves disease can coexist.

Chronic progressive external ophthalmoplegia:

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 Patients generally do not complain of diplopia in the presence of very restricted extraocular
movements, which is typically more severe than seen in MG.

Retinal degeneration can coexist, and more generalized muscle weakness can occur later in the
disease course.

Cranial neuropathy:

MG never involves the pupil, distinguishing it from Horners syndrome or a IIIrd nerve palsy.

MG may mimic VIth nerve palsy with isolated lateral rectus weakness, but may be distinguished
by fatigability and lack of pain.

MG may produce a pseudo-internuclear ophthalmoplegia with isolated medial rectus weakness.

Patients with true internuclear ophthalmoplegia usually have spared convergence.

Brainstem pathology:

Tumors, strokes, aneurysms, carcinomatous meningitis, and so on.

Diagnosed with head imaging (CT, MRI) and cerebrospinal fluid (CSF) studies.

Generalized MG

LambertEaton myasthenic syndrome (LEMS):

LEMS has more prominent lower extremity weakness than MG. Ocular and bulbar symptoms
are less prominent in LEMS than in MG and are seldom the presenting symptoms.

Autonomic symptoms are common: dry mouth, impotence, decreased sweating.

Voltage-gated calcium channel (VGCC) antibodies are present in 90% of patients with LEMS.

Low amplitude CMAPs, a decremental response to slow repetitive stimulation studies (25 Hz)
and post-exercise facilitation (10 seconds of exercise) of the CMAP amplitude of more than 100%
are characteristic of LEMS (see section on LEMS).

Motor neuron disorders:

Extraocular muscle weakness and ptosis are generally not present.

Upper and lower motor neuron signs coexist: muscle fasciculations, atrophy, hyper-reflexia,
Babinski sign, and hypertonia.

Widespread evidence of motor nerve denervation and reinnervation on needle EMG.

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Botulism:
Rapid onset of a descending pattern of weakness including ocular, bulbar, respiratory, and
generalized weakness.
May have pupillary and autonomic involvement.

Low CMAP amplitudes and post-exercise facilitation of CMAP amplitude to a lesser degree than
seen in LEMS are characteristic.

Needle EMG may demonstrate fibrillation potentials and short duration polyphasic motor unit
action potentials (MUPs) as a result of chemodenervation.

Drug-induced MG:
Penicillamine: induces production of acetylcholine antibodies; symptoms resolve within 312
months after withdrawal of the medicine.
Congenital MG (see below):
Long history of symptoms (often from infancy or childhood) with gradual progression.
AChR or anti-MuSK antibodies are absent.
May have a positive family history.

May have characteristic findings on NCS (repetitive CMAP in slow channel syndrome or
acetylcholineesterase deficiency).

Requires genetic testing or specialized electrophys- iologic testing on intercostal or anconeus

muscle.
Not responsive to immunotherapies.

2.9 Treatment
First-line
Cholinesterase inhibitors
Increase the amount of acetylcholine available for binding at the NMJ.
Provide symptomatic relief, but do not affect disease progression.
Rarely provide complete or sustained benefit.
Initial dose is 30 mg every 46 hours which is increased to maximize benefit and minimize
side- effects. Dosages exceeding 120 mg every 34 hours are rarely beneficial and may place
patient at risk for cholinergic overdose.
Dose limiting side-effects include stomach cramps, diarrhea, excessive perspiration,
salivation, brady- cardia, nausea, vomiting, and increased bronchial secretions.
Cholinergic overdose (dosages exceeding 450 mg daily) can induce worsening muscle
weakness and is usually associated with muscarinic symptoms.

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 Corticosteroids
Prednisone is the most commonly used immune directed therapy:
Induces marked improvement or remission in > 70% of patients.

Typically started at a high daily dose (0.751.0 mg/kg daily) and gradually tapered off over
months or continued at a low daily or alternate day dose.

One- third to one-half of patients experience a transient worsening of symptoms

approximately 12 weeks after initiation. Some advocate gradual initiation of prednisone to
reduce this risk.
Beneficial effects start in 24 weeks and peak after 612 months.
Side-effects are common (Tables 117, 118).

Tip : Vigilant monitoring of corticosteroid side-effects is indicated with serum glucose and vitamin
D levels, bone density test, cataract screening, and so on. Most patients taking prednisone for 3
months should also take daily calcium, vitamin D, and a bisphosphonate.
Thymectomy
The only absolute indication for thymectomy is thymoma.
Optimization of MG treatment should be obtained prior to thymectomy in all cases.
Thymectomy is considered an option for patients with generalized disease who are less than 60
years of age.

Although thymectomy may increase the likelihood for improvement or remission, rigorous
clinical studies are lacking.
There is no evidence to support thymectomy in MuSK myasthenia.

Second-line
Chronic immunotherapy (Table 119)
Azathioprine (AZA):

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 Interferes with B- and T-cell proliferation by inhibiting purine synthesis.
Used for corticosteroid sparing.
Full benefit of treatment may not be reached until > 1 year.

Initiated at 50 mg daily or twice daily and increased by 50 mg per week until maintenance dose
of 23 mg/kg/day.

Major side-effects are hepatotoxicity and leukopenia. Therefore, liver function tests and white
blood cell count should be monitored. A flu-like reaction may appear a few weeks after initiation
(or in some cases much later) which may be severe and associated with neutropenia. AZA must
be promptly discontinued.
Risk for certain malignancies, particularly hematopoietic malignancies, may increase in long-
term treatment with AZA.
Mycophenolate mofetil (MMF):
Interferes with B- and T-cell proliferation by inhibiting purine synthesis.
A double-blind, placebo-controlled pilot study showed a promising trend, favoring benefit of
MMF compared to placebo. However, two recent double-blind, placebo-controlled studies showed
that there was no significant benefit of mycophenolate plus corticosteroids over corticosteroid
treatment alone. However, patients were only followed for 12 and 36 weeks in these two studies,
and the mechanism of action of mycophenolate as well as experience with AZA and other
immunosuppressive drugs suggest that longer treatment may be necessary for peak clinical effect.
Typical starting dose is 1000 mg twice daily.
A potentially serious side-effect is myelosuppres- sion, and so complete blood cell count should
be monitored.

Third-line
Cyclosporine

Cyclosporine causes disruption of the calcineurin signaling pathway and blocking of interleukin-
2 synthesis leading to disruption of T cell proliferation.

Generally utilized as a corticosteroid-sparing agent if AZA or MMF fails. It has been

demonstrated to be effective in both immunosuppressant-nave patients and in combination with
corticosteroid.

The initial dose is 35 mg/kg divided to twice daily regimen. Onset of benefit may take 12
months

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 Side-effects include tremor, excessive hair growth, anemia, nephrotoxicity, and hypertension;
renal function should be monitored and trough cyclosporine levels should be followed regularly
with a goal of 75150 ng/ml.
Cyclosporine may increase the risk of certain malignancies.
Tacrolimus

Tacrolimus blocks T cell proliferation by inhibiting the calcineurin signaling pathway. In a pilot
study, patients on tacrolimus required less plasma exchange and corticosteroid.
Typical low-dose therapy is 35 mg/day divided into bid dosing.

Side-effects: tremor, hyperglycemia, hypercholester- olemia, hypertension, nephrotoxicity, and

hair loss.
Rituximab
Monoclonal antibody that targets CD20+ B lymphocytes.

Both anti-AChR antibody-positive and anti-MuSK- positive refractory MG patients appear to

respond to rituximab without significant adverse effects.

Experience with this drug comes from small case series; a large randomized trial is needed to
assess its effectiveness in MG.
Short-term immunotherapy
Plasma exchange

Plasma exchange (PE) temporarily removes circulating antibodies. Improvement from PE is

generally observed after three to six exchanges; typically a 34 liter exchange of plasma is given
every other day for six exchanges. It is mainly used in patients who are in crisis, prior to thymec-
tomy or in combination with high-dose corticosteroids to prevent a steroid-induced exacerbation.
The effect of PE begins to taper after 2 weeks.

Adverse effects include hypotension, hypocalcemia, reduction in coagulation factors, thrombosis,

and infection associated with central venous access.
IV immunoglobulin

IV immunoglobulin (IVIG) is used in a similar fashion to PE. It is also used serially in patients
who have not obtained an adequate response with typical immunosup- pressants. Initial dose is 1
2 g/kg divided over 15 days followed by 0.51 g/kg every 34 weeks as required.

The efficacy of IVIG was evaluated in a randomized, placebo-controlled trial in 2007; the IVIG-
treated group had clinically significant improvement on the Quantitative Myasthenia Gravis
(QMG) Score at 14 and 28 days15. IVIG and PE were shown to be equally effi- cacious in MG

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exacerbation, although IVIG was better tolerated. Arguably, suboptimal regimens of PE were uti-
lized in the studies comparing PE and IVIG and the onset of effect was also not assessed.
Experience would dictate that PE may be more efficacious in situations of crisis.
Side-effects include flu-like reaction, headache, aseptic meningitis, renal failure, and stroke

2.10 Complication
Complications of myasthenia gravis are treatable, but some can be life-threatening.

Myasthenic crisis
Myasthenic crisis is a life-threatening condition that occurs when the muscles that control
breathing become too weak to do their jobs. Emergency treatment is needed to provide mechanical
assistance with breathing. Medications and blood-filtering therapies help people to again breathe
on their own.

Thymus tumors
About 15 percent of people with myasthenia gravis have a tumor in their thymus, a gland under
the breastbone that is involved with the immune system. Most of these tumors, called thymomas,
aren't cancerous (malignant).

Other disorders
People with myasthenia gravis are more likely to have the following conditions:

Underactive or overactive thyroid. The thyroid gland, which is in the neck, secretes hormones that
regulate your metabolism. If your thyroid is underactive, you may have difficulties dealing with
cold, weight gain and other issues. An overactive thyroid can cause difficulties dealing with heat,
weight loss and other issues.

Autoimmune conditions. People with myasthenia gravis may be more likely to have autoimmune
conditions, such as rheumatoid arthritis or lupus.

2.10 Prognosis
Patients who present with ocular complaints have an 8085% chance of generalizing.
There is some evidence that treatment with corticosteroids may decrease this risk.
The mortality rate from MG was more than 30% before the 1960s, but with the onset of modern
critical care and immunosuppressive therapy life expectancy in MG now approaches normal.
At least 80% of patients are able to experience significant improvement in their symptoms;
however, fixed weakness may develop later in the disease course if muscle weakness is not treated
optimally.
Few patients are able to wean off immunotherapy completely.

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 REFERENCES

1. National Institute of Neurological Disorders and Stroke. Myasthenia Gravis. March, 2017
https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-
Sheets/Myasthenia-Gravis-Fact-Sheet#3153_2
2. Shah, AK et.al, Myasthenia Gravis. Medscape. WebMD. 23 March 2016
http://emedicine.medscape.com/article/1171206-overview
3. Lindsay, KW et.al, Neurology and Neurosurgery Illustrated 5th. Elsevier 2010.
4. Gorelick, PB et.al, Clinical Neurology 2nd edition. CRC Press. Newyork 2014.
5. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle
Nerve. 2008 Feb. 37(2):141-9.

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