MYASTHENIA GRAVIS IS A AUTO IMMUNE DISORDER EFFECTING NEUROMUSCULAR TRANMISSION.

1. MYASTHENIA GRAVIS
PRESENTED BY:
K.PRANAY KUMAR
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2. Myasthenia
Gravis
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3. Preamble
 Overview
 Pathophysiology
 Clinical presentation
 Signs and symptoms
 Diagnosis
 Treatment and management
 Prognosis
 Current research
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4. OVERVIEW
• The name myasthenia gravis, which is Latin and
Greek in origin, literally means "grave muscle
weakness.“
• Antibody-mediated autoimmune disease of the
neuromuscular junction.
• The hallmark of myasthenia gravis is muscle
weakness that increases during periods of activity
and improves after periods of rest.
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5. • Certain muscles such as those that control eye and
eyelid movement, facial expression, chewing,
talking, and swallowing are often, but not always,
involved in the disorder.
• The muscles that control breathing and neck and
limb movements may also be affected.
• Myasthenia gravis occurs in all ethnic groups and
both sexes.
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6. • It most commonly affects women under 40 and
people from 50 to 70 years old of either sex, but it
has been known to occur at any age. Younger
patients rarely have thymoma.
• Myasthenic crisis a severe generalized
quadriparesis or life-threatening respiratory
muscle weakness, occurs in about 15 to 20% of
patients at least once in their life. Once
respiratory insufficiency begins, respiratory
failure may occur rapidly.
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7. PATHOPHYSIOLOGY
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8. Pathophysiology
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9. Myasthenia gravis
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10. 2/19/2017 10MYASTHENIA GRAVIS

11. The Thymus in Myasthenia Gravis
 10% of patients with myasthenia gravis have a thymic tumor
and 70% have hyperplastic changes that indicate an active
immune response.
 The thymus contains all the necessary elements for the
pathogenesis of myasthenia gravis: myoid cells that express
the AChR antigen, antigen presenting cells, and
immunocompetent T-cells.
 The thymus is the central organ for immunological self-
tolerance, it is reasonable to suspect that thymic
abnormalities cause the breakdown in tolerance that causes
an immune-mediated attack on AChR in myasthenia gravis.
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12. The Thymus in Myasthenia Gravis
 However, it is still uncertain whether the role of the thymus in
the pathogenesis of myasthenia gravis is primary or secondary.
 Most thymic tumors in patients with myasthenia gravis are
benign, well-differentiated and encapsulated, and can be
removed completely at surgery.
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13. Patients with thymoma usually have more severe
disease, higher levels of AChR antibodies, and
more severe EMG abnormalities than patients
without thymoma.
Scientists believe the thymus gland may give
incorrect instructions to developing immune cells,
ultimately resulting in autoimmunity and the
production of the acetylcholine receptor
antibodies, thereby setting the stage for the attack
on neuromuscular transmission.
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14. CLINICAL PRESENTATION
 Congenital Myasthenia Gravis
 Acquired Myasthenia Gravis
 Neonatal myasthenia
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15. Congenital Myasthenia Gravis
• Rare autosomal recessive disorder that begins in childhood; it
results from structural abnormalities in the postsynaptic
receptor rather than an autoimmune disorder.
Ophthalmoplegia is common.
• Rarely, children may show signs of congenital myasthenia or
congenital myasthenic syndrome.
• These are not autoimmune disorders, but are caused by
defective genes that produce abnormal proteins instead of
those which normally would produce acetylcholine, acetyl
cholinesterase, or the acetylcholine receptor and other
proteins present along the muscle membrane.
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16. Acquired Myasthenia Gravis
• The immune system is destroying neuromuscular
junctions as if they were foreign invaders.
• Therapy centers on stopping this immune reaction.
This is done with a combination of immuno-
suppressive agents and medications to inhibit
acetylcholinesterase.
• Acquired myasthenia gravis can be further divided
into four subtypes:
1. Focal - only one body part ,usually the
esophagus, is involved
2. Generalized - all skeletal muscle involved
3. Fulminating - rapidly progressive and usually
fatal
4. Paraneoplastic - where a thymoma is present
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17. Neonatal myasthenia
• Affects 12% of infants born to women with
myasthenia gravis. It is due to IgG antibodies that
passively cross the placenta. It causes generalized
muscle weakness, which resolves in days to weeks as
antibody titers decline. Thus, treatment is usually
supportive.
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18. SIGNS AND SYMPTOMS
• Painless weakness of specific muscles, not fatigue.
• The muscle weakness becomes progressively worse during
periods of physical activity, and improves after periods of rest.
 Typically, the weakness and fatigue are worse towards the end
of the day. MG generally starts with ocular (eye) weakness; it
might then progress to a more severe generalized form,
characterized by weakness in the extremities or while
performing basic life functions.
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19. At a Glance
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20. Eyes
• In about two-thirds of individuals, the initial symptom of MG is related to
the muscles around the eye.
• There may be eyelid drooping (ptosis due to weakness of levator palpebrae
superioris) and double vision (diplopia due to weakness of the extraocular
muscles).
• Eye symptoms tend to get worse when watching television, reading or
driving, particularly in bright conditions.Consequently, some affected
individuals choose to wear sunglasses.
• The term "ocular myasthenia gravis" describes a subtype of MG where
muscle weakness is confined to the eyes, i.e. extra ocular muscles, levator
palpebrae superioris and orbicularis oculi. Typically, this subtype evolves
into generalized MG, usually after a few years.
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21. Eating
• Weakness of the muscles involved in swallowing may lead to swallowing
difficulty (dysphagia).
• Typically, this means that some food may be left in the mouth after an
attempt to swallow, or food and liquids may regurgitate into the nose rather
than go down the throat (velopharyngeal insufficiency).
• Weakness of the muscles that move the jaw (muscles of mastication) may
cause difficulty chewing.
• In individuals with MG, chewing tends to become more tiring when
chewing tough, fibrous foods. Difficulty in swallowing, chewing and
speaking is the first symptom in about one-sixth of individuals.
Voice
• Weakness of the muscles involved in speaking may lead to dysarthria and
hypophonia. Speech may be slow and slurred,[9] or have a nasal quality. In
some cases a singing hobby or profession must be abandoned.[8]
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22. Head and neck
• Due to weakness of the muscles of facial expression and muscles of
mastication, there may be facial weakness, manifesting as inability to hold
the mouth closed (the "hanging jaw sign"), and a snarling appearance when
attempting to smile.
• Together with drooping eyelids, facial weakness may make the individual
appear sleepy or sad. There may be difficulty in holding the head upright.
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23. Respiratory muscles
• The muscles that control breathing (dyspnea) and limb
movements can also be affected, but rarely do these present as
the first symptoms of MG, and they develop over months to
years.
• In a myasthenic crisis, a paralysis of the respiratory muscles
occurs, necessitating assisted ventilation to sustain life.
• Crisis may be triggered by various biological stressors such as
infection, fever, an adverse reaction to medication, or emotional
stress.
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24. MYASTHENIA GRAVIS FOUNDATION OF AMERICA
CLINICAL CLASSIFICATION
Class Description
I
Any eye muscle weakness, possible ptosis, no other evidence of muscle
weakness elsewhere
II Eye muscle weakness of any severity, mild weakness of other muscles
IIa Predominantly limb or axial muscles
IIb Predominantly bulbar and/or respiratory muscles
III Eye muscle weakness of any severity, moderate weakness of other muscles
IIIa Predominantly limb or axial muscles
IIIb Predominantly bulbar and/or respiratory muscles
IV Eye muscle weakness of any severity, severe weakness of other muscles
IVa Predominantly limb or axial muscles
IVb Predominantly bulbar and/or respiratory muscles
V Intubation needed to maintain airway
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25. Myasthenia gravis in animals
It is fairly common in mature dogs, especially German Shepherds, Golden
Retrievers, and Labrador Retrievers, but is uncommon in cats.
Three clinical forms exist in animals.
• The generalized form, which affects 57% of dogs with acquired
myasthenia, is characterized by exercise-induced stiffness, tremors, and
weakness that resolve with rest. However, weakness is not always
associated with exercise. Megaesophagus is common in the generalized
form.
• Focal myasthenia (43% of affected dogs) presents as facial,
pharyngeal, or oesophageal weakness without generalized weakness.
• Fulminant myasthenia least common, which presents as acute, flaccid
paralysis and megaesophagus, which rapidly progresses to respiratory
paralysis and is usually fatal.
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27. DIAGNOSIS
History
Physical exam
Clinical investigations
Tensilon test
Serum antibody
(x-AChR & X-MUSK)
Ice test
EMG
(RNS & SFEMG)
Imaging
( X ray,CT,MRI)
Pulmonary function test
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28. History
• The first steps of diagnosing myasthenia gravis include a review of the
individual's medical history, and physical and neurological examinations.
• A characteristic of MG is that patients have weakness that comes on with
activity and improves following rest.
Physical examination
• During a physical examination to check for MG, a doctor might ask the
potentially affected person to look at a fixed point for 30 seconds and to
relax the muscles of their forehead.
• This is done because a person with MG and ptosis of their eyes might be
involuntarily using their forehead muscles to compensate for the weakness
in their eyelids.
• The clinical examiner might also try to elicit the "curtain sign" in a patient
by holding one of the person's eyes open, which in the case of MG will lead
the other eye to close.
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29. • Weakness caused by abnormal neuromuscular transmission
characteristically improves after intravenous administration of
edrophonium chloride, commonly referred to as the Tensilon®
Test.
• The edrophonium test uses intravenous administration of
edrophonium chloride to very briefly relieve weakness in people
with myasthenia gravis.
• The drug blocks the degradation (breakdown) of acetylcholine
and temporarily increases the levels of acetylcholine at the
neuromuscular junction.
• Some patients who do not respond to intravenous edrophonium
chloride may respond to intramuscular neostigmine, because of its
longer duration of action. Intramuscular neostigmine is
particularly useful in infants and children whose response to
intravenous edrophonium chloride may be too brief for adequate2/19/2017 29MYASTHENIA GRAVIS

30. • Applying ice for two to five minutes to the muscles reportedly
has a sensitivity and specificity of 76.9% and 98.3%,
respectively, for the identification of MG.
• Acetylcholinesterase is thought to be inhibited at the lower
temperature, and this is the basis for this diagnostic test.
• This generally is performed on the eyelids when a ptosis is
present and is deemed positive if there is a ≥2mm raise in the
eyelid after the ice is removed.
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31. • A special blood test can detect the presence of acetylcholine receptor
antibodies. Most patients with myasthenia gravis have abnormally
elevated levels of these antibodies.
• Recently, a second antibody—called the anti-MuSK antibody—has
been found in about 30 to 40 percent of individuals with myasthenia
gravis who do not have acetylcholine receptor antibodies.
• Acetylcholine Receptor Antibody— a blood test for the abnormal
antibodies can be performed to see if they are present. Approximately
85% of MG patients have this antibody and, when detected with an
elevated concentration the AChR antibody test is strongly indicative of
MG.
• Anti-MuSK Antibody testing----a blood test for the remaining 15% of
MG patients who have tested negative for the acetylcholine antibody.
These patients have seronegative (SN) MG. About 40% of patients with
SNMG test positive for the anti-MuSK antibody.
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32. Single fibre electromyography(SFEMG)
• SFEMG measures the electrical potential of muscle cells when single
muscle fibre are stimulated by electrical impulse. Muscle fibres in
myasthenia gravis, as well as other neuromuscular disorders, do not
respond to electrical stimulation compared to muscles from normal
individuals.
Repetitive Nerve Stimulation (RNS)
• This test records weakening muscle responses when the nerves are
repetitively stimulated by small pulses of electricity.
• The amplitude of the compound muscle action potential (CMAP) elicited
by repetitive nerve stimulation is normal or only slightly reduced in normal
ones.
• The amplitude of the fourth or fifth response to a train of low frequency
nerve stimuli falls at least 10% from the initial value in myasthenic
patients. This decrementing response to RNS is seen more often in
proximal muscles, such as the facial muscles, biceps, deltoid, and trapezius
than in hand muscles. A significant decrement to RNS in either a hand or
shoulder muscle is found in about 60% of patients with myasthenia gravis.2/19/2017 32MYASTHENIA GRAVIS

33. Repetitive Nerve Stimulation (RNS)
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34. • A chest X-ray may identify widening of the mediastinum suggestive of
thymoma.
• Diagnostic imaging of the chest, using computed tomography (CT) or
magnetic resonance imaging (MRI), may be used to identify the presence
of a thymoma.
• MRI of the cranium and orbits may also be performed to exclude
compressive and inflammatory lesions of the cranial nerves and ocular
muscles
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35. • Pulmonary function testing, which measures breathing
strength, helps to predict whether respiration may fail and lead
to a myasthenic crisis.
• The forced vital capacity may be monitored at intervals to
detect increasing muscular weakness.
• Acutely, negative inspiratory force may be used to determine
adequacy of ventilation; it is performed on those individuals
with MG
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36. TREATMENT
Anticholinesterases
Immunosuppressants
Plamsapheresis
IVIG
Thymectomy
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37. Cholinesterase Inhibitors
• ChE inhibitors retard the enzymatic hydrolysis of ACh at
cholinergic synapses, so that ACh accumulates at the
neuromuscular junction and its effect is prolonged.
• ChE inhibitors cause considerable improvement in some patients
and little to none in others. Strength rarely returns to normal.
Pyridostigmine bromide (Mestinon) and neostigmine bromide
(Prostigmin) are the most commonly used ChE inhibitors.
• The need for ACh inhibitors varies from day-to-day and during
the same day in response to infection, menstruation, emotional
stress, and hot weather. Different muscles respond differently;
with any dose, certain muscles get stronger, others do not change.
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38. • Adverse effects of ChE inhibitors may result from ACh
accumulation at muscarinic receptors on smooth muscle and
autonomic glands and at nicotinic receptors of skeletal
muscle. Gastrointestinal complaints are common;
queasiness, loose stools, nausea, vomiting, abdominal
cramps, and diarrhea. Increased bronchial and oral
secretions are a serious problem in patients with swallowing
or respiratory insufficiency.
• Cholinergic crisis is muscular weakness that can result when
the dose of anticholinesterase drugs (eg, neostigmine,
pyridostigmine) is too high. A mild crisis may be difficult to
differentiate from worsening myasthenia. Severe cholinergic
crisis can usually be differentiated because it, unlike
myasthenia gravis, results in increased lacrimation and
salivation, tachycardia, and diarrhoea.
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39. Corticosteroids
• Marked improvement or complete relief of symptoms occurs in more than
75% of patients treated with prednisone.
• Much of the improvement occurs in the first 6 to 8 weeks, but strength may
increase to total remission in the months that follow.
• The best responses occur in patients with recent onset of symptoms, but
patients with chronic disease may also respond.
• Patients with thymoma have an excellent response to prednisone before or
after removal of the tumor.
• The most predictable response to prednisone occurs when treatment begins
with a daily dose of 1.5 to 2 mg/kg/day. About one-third of patients become
weaker temporarily after starting prednisone, usually within the first 7 to 10
days, and lasting for up to 6 days.
• Treatment can be started at low dose to minimize exacerbations; the dose is
then slowly increased until improvement occurs. Exacerbations may also
occur with this approach and the response is less predictable.
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40. Immunosuppressant Drugs
• Azathioprine
reverses symptoms in most patients but the effect is delayed by
4 to 8 months. Once improvement begins, it is maintained for
as long as the drug is given, but symptoms recur 2 to 3 months
after the drug is discontinued or the dose is reduced below
therapeutic levels. Patients who fail corticosteroids may
respond to azathioprine and the reverse is also true. Some
respond better to treatment with both drugs than to either
alone. Because the response to azathioprine is delayed, both
drugs may be started simultaneously with the intent of rapidly
tapering prednisone when azathioprine becomes effective.
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41. • Cyclosporine
inhibits predominantly T-lymphocyte-dependent immune
responses. Most patients with myasthenia gravis improve 1 to 2
months after starting cyclosporine and improvement is
maintained as long as therapeutic doses are given. Maximum
improvement is achieved 6 months or longer after starting
treatment. After achieving the maximal response, the dose is
gradually reduced to the minimum that maintains improvement.
Renal toxicity and hypertension, the important adverse
reactions of cyclosporine. Many drugs interfere with
cyclosporine metabolism and should be avoided or used with
caution.
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42. Plasma Exchange
• Plasma exchange is used as a short-term intervention for
patients with sudden worsening of myasthenic symptoms for
any reason, to rapidly improve strength before surgery, and as
a chronic intermittent treatment for patients who are refractory
to all other treatments.
• The need for plasma exchange, and its frequency of use is
determined by the clinical response in the individual patient.
Almost all patients with acquired myasthenia gravis improve
temporarily following plasma exchange. Maximum
improvement may be reached as early as after the first
exchange or as late as the fourteenth.
• Improvement lasts for weeks or months and then the effect is
lost unless the exchange is followed by thymectomy or
immunosuppressive therapy. Most patients who respond to the
first plasma exchange will respond again to subsequent
courses. Repeated exchanges do not have a cumulative benefit.
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43. Intravenous Immune Globulin (IVIG)
• Several groups have reported a favorable response to high-dose
(2 grams/kg infused over 2 to 5 days) IVIG. Possible
mechanisms of action include down-regulation of antibodies
directed against AChR and the introduction of anti-idiotypic
antibodies.
• Improvement occurs in 50 to 100% of patients, usually
beginning within 1 week and lasting for several weeks or
months. The common adverse effects of IVIG are related to the
rate of infusion.
• The mechanism of action is not known but is probably non-
specific down regulation of antibody production.
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44. Thymectomy
• Thymectomy is recommended by many physicians for most patients with
myasthenia gravis. Most reports do not correlate the severity of weakness
before surgery and the timing or degree of improvement after thymectomy.
• The maximal favorable response generally occurs 2 to 5 years after surgery.
However, the response is relatively unpredictable and significant
impairment may continue for months or years after surgery.
• Sometimes, improvement is only appreciated in retrospect. The best
responses to thymectomy are in young people early in the course of their
disease, but improvement can occur even after 30 years of symptoms.
Patients with disease onset after the age of 60 rarely show substantial
improvement from thymectomy.
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45. Drugs to Avoid
• Many different drugs have been associated with worsening
myasthenia gravis (MG). However, these drug associations do
not necessarily mean that a patient with MG should not be
prescribed these medications because in many instances the
reports are very rare and in some instances they might only be
a “chance” association.
• Some of these drugs may be necessary for a patient’s
treatment. Therefore, some of these drugs should not
necessarily be considered “off limits” for MG patients.
• Careful thought needs to go into decisions about
prescription. It is important that the patient notify his or her
physicians if the symptoms of MG worsen after starting any
new medication.
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46. Myasthenia
weakness
exaggerated
Quinine
Magnesium
Pencillamine
Erythromycin
Azithromycin
Ciprofolxacin
Levofloxacin
Ofloxacin
Gatifloxacin
Non-depolarising
muscle relaxants
(pancuronium)
Propanol
Atenolol
Local anaesthetic
(lignocaine)
Streptomycin
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47. PROGNOSIS
• With treatment, most individuals with myasthenia can
significantly improve their muscle weakness and lead normal
or nearly normal lives.
• Some cases of myasthenia gravis may go into remission—
either temporarily or permanently—and muscle weakness may
disappear completely so that medications can be discontinued.
• Stable, long-lasting complete remissions are the goal of
thymectomy and may occur in about 50 percent of individuals
who undergo this procedure.
• In a few cases, the severe weakness of myasthenia gravis may
cause respiratory failure, which requires immediate emergency
medical care.
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48. RESEARCH
• Researchers are seeking to learn what causes the autoimmune
response in myasthenia gravis, and to better define the
relationship between the thymus gland and myasthenia gravis.
• Different drugs are being tested, either alone or in combination
with existing drug therapies, to see if they are effective in
treating myasthenia gravis. One study is examining the use of
methotrexate therapy in individuals who develop symptoms
and signs of the disease while on prednisone therapy.
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49. References:
1. Werner Hoch, John McConville,Sigrun Helms,John Newsom,Arthur
Melms & Angela Vincent(2001): Auto-antibodies to the receptor
tyrosine kinase MuSK in patients with myasthenia gravis without
acetylcholine receptor antibodies.
2. Curtis Wells Dewey, Cleta Sue Bailey, G. Diane Shelton, Philip H.
Kass, and G. H. Cardinet(1995):Clinical Forms of Acquired
Myasthenia Gravis in Dogs.
3. Jon M. Linderstrom, PhD, Marjorie E. Seybold,
MD,(2002):Antibody to acetylcholine receptor in myasthenia gravis
4. The Merck Veterinary Manual(9th edition)
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50. THANK YOU
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