MYASTHNIA GRAVIS

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MYASTHENIA GRAVIS

PRESENTED BY:K.PRANAY KUMAR

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Myasthenia Gravis

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Preamble Overview Pathophysiology Clinical presentation Signs and symptoms Diagnosis Treatment and management Prognosis Current research

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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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• 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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• 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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PATHOPHYSIOLOGY

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Pathophysiology

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Myasthenia gravis

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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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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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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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CLINICAL PRESENTATION

Congenital Myasthenia Gravis Acquired Myasthenia Gravis Neonatal myasthenia

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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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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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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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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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At a Glance

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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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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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https://en.wikipedia.org/wiki/Myasthenia_gravis

https://en.wikipedia.org/wiki/Myasthenia_gravis


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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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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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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https://en.wikipedia.org/wiki/Ptosis_(eyelid)


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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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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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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The Edrophonium Chloride (Tensilon®) Test • 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 adequate observation.

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Ice test• 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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Serum antibody testing • 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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ElectromyographySingle 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.

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Repetitive Nerve Stimulation (RNS)

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Diagnostic imaging

• 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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Pulmonary function test

• 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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TREATMENT

Anticholinesterases

Immunosuppressants

Plamsapheresis

IVIG

Thymectomy

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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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• 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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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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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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• 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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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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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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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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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. 2/19/2017


Myasthenia weakness

exaggerated

Quinine Magnesium

Pencillamine

ErythromycinAzithromycin

CiprofolxacinLevofloxacin

OfloxacinGatifloxacin

Non-depolarising muscle relaxants (pancuronium)

PropanolAtenolol

Local anaesthetic (lignocaine)

Streptomycin

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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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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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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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THANK YOU

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MYASTHNIA GRAVIS

Health & Medicine

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