DEPARTMENT OF NEUROLOGY MARDI WALUYO HOSPITAL, LAMPUNG

MYASTHENIA GRAVIS
M IZZUN NASHEEF B M HASMURI LAILA ATIFAH BT KAMALUDIN SITI NURAIN BT JAMALUDIN FACULTY OF MEDICINE, UKRIDA

CONTENTS Preface Chapter I Chapter II

Introduction Definition Anatomy & Physiology Epidemiology Etiology Pathogenesis Clinical Findings Diagnosis Differential Diagnosis Treatment Prognosis

3 4 5 6 8 9 10 12 16 18 19 22 23 24

Chapter III Chapter IV

Conclusion References

PREFACE

Medicine is an art. As new search and clinical broaden our knowledge, brief changes in treatment and therapy to the patient must be really up to date. Thus, in order to be a competent doctor nowadays, we have to be current in every aspect towards our patients. As assigned by our lecturer regarding on Myasthenia Gravis, accomplished by us, co assistant at the department of Neurology, Mardi Waluyo Hospital, Lampung is intended to enhance and integrate our knowledge on neurology itself. This disease seems so peculiar but prompt action must be evaluated to diagnose this as soon as possible. In this opportunity, we would like to thank our beloved consultant for welcoming us with his warm and generous knowledge that we shared all along these days, dr. Hadi Soeprapto, Sp. S from the department of Neurology, Mardi Waluyo Hospital, Lampung. Countless information, clinical skills and sweet memories during our internship here will be blossomed in our thought forever. Hopefully, this assignment will benefit us as a skilled doctor in the future . Regards, Izzun Nasheef Laila Atifah Siti Nurain January 2011

CHAPTER I INTRODUCTION
Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. The name myasthenia gravis, which is Latin and Greek in origin, literally means "grave muscle weakness." With current therapies, however, most cases of myasthenia gravis are not as "grave" as the name implies. In fact, most individuals with myasthenia gravis have a normal life expectancy. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. 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. [1] Two fundamentally different pathological processes are associated with disease at the neuromuscular junction. First, acquired disorders in which auto antibodies are directed against nerve or muscle ion channels. Second, and much rarer, inherited conditions in which the defect may be pre- or postsynaptic. These acquired and inherited conditions share some symptomatology. The most important are the autoimmune diseases: myasthenia gravis, the LambertEaton myasthenia syndrome, and acquired neuromyotoniadisorders for which therapy is available. [1,2]

Figure I : Generalized myasthenia gravis, key features. A Ptosis B Attempted gaze to the right. Only right eye abducts incompletely. C Demonstrates proximal weakness upon attempt to raise the arms. D Holding the arms and fingers extended the extensor muscles weaken and finger drop occurs. 4

CHAPTER II DEFINITION

Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. [2] Myasthenia Gravis is caused by a defect of neuromuscular transmission owing to antibody-mediated attack on nicotinic acetylcholine receptors (AChR) at neuromuscular junctions. It is characterized by fluctuating weakness that is improved by inhibitors of cholinesterase.

Figure II : Comparison between normal nerve transmission and Myasthenia Gravis in the neuromuscular junction

ANATOMY & PHYSIOLOGY

During neuromuscular transmission, anatomically there are three main components to the neuromuscular junction. The presynaptic component is the motor nerve terminal, which contains packages (quanta) of acetylcholine, each of which contains several thousand molecules of acetylcholine. This is separated from the postsynaptic acetylcholine receptors, which sit atop the terminal expansions of the junctional folds of the muscle fibre membrane, by the synaptic space. The nerve fibre membrane contains voltage-gated sodium, potassium, and calcium channels. Voltagegated sodium channels are also present postsynaptically, at the base of the clefts of the junctional folds. [1,2]

Figure III : Neuromuscular junction The nicotinic acetylcholine receptor is a pentameric structure composed of four different subunits a, b, g, and in fetal muscle and a, b, e, and in adult muscle. It is configured to produce a central ion channel. Structurally and functionally there are similarities to voltage-gated ion channels, but the acetylcholine receptor is a ligand gated channel, the ligand being acetylcholine. Depolarization of the motor nerve terminal is dependent upon voltage-gated sodium channels. Repolarization is the result of inactivation of these sodium channels and opening of voltage-gated potassium channels. During depolarization, voltage gated calcium channels openthe influx of calcium ions into the nerve terminal triggers release (by exocytosis) of quanta of acetylcholine. If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. [2]

The acetylcholine binds to the a-subunits of the acetylcholine receptors. This alters the conformation of the channel allowing cations (mainly sodium) to enter the muscle fibre. This influx generates the end-plate potential, which in turn activates voltage-gated sodium channels. These trigger the action potential which is propagated through the muscle fibre and initiates contraction. Spontaneous release of individual quanta of acetylcholine, as opposed to mass release triggered by a nerve action potential, gives rise to miniature end-plate potentials, which can be recorded by microelectrode. These are of insufficient amplitude to trigger an action potential in the muscle fibre membrane. [1,2] The action of acetylcholine on acetylcholine receptors is terminated by the hydrolysis of acetylcholine by the enzyme acetyl cholinesterase and by diffusion of ACh away from the receptor.

EPIDEMIOLOGY
Myasthenia gravis is not rare, having a prevalence of at least 1 in 7500. It affects individuals in all age groups, but peaks of incidence occur in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are more frequently affected, in a ratio of about 3 : 2. The female bias is even more marked in younger-onset cases, whereas over the age of 50 years male cases predominate. A rather different pattern is seen in people of Asian origin; prepubertal onset is very common, the disease is often purely ocular, and there is a strong association with HLA DRw9. Myasthenia Gravis is a common disease. An apparent increase in the incidence of the disease in recent years is probably owing to improved diagnosis. According to Phillips and Torner (1996), the prevalence rate is 14 per 100,000 (or about 17,000 cases) in the United States. Before age 40 years, the disease is three times more common in women, but at older ages both sexes are equally affected.

Familial cases are rare : single members of pairs of fraternal twins and several sets of identical twins have been affected. Young women with MG tend to have HLA-B8, -DR3, and -DQB1* 0102 haplotypes; in young Japanese women HLA-A12 is prominent. These observations imply the presence of a linked immune response gene that encodes a protein involved in the autoimmune response. First-degree relatives show an unusual incidence of other autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, thyroid disease) and HLA-B8 haplotype. [1,2]

ETIOLOGY
Myasthenia gravis is caused by a defect in the transmission of nerve impulses to muscles. It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junctionthe place where nerve cells connect with the muscles they control. Normally when impulses travel down the nerve, the nerve endings release a neurotransmitter substance called acetylcholine. Acetylcholine travels from the neuromuscular junction and binds to acetylcholine receptors which are activated and generate a muscle contraction. [2,3] In myasthenia gravis, antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle contraction from occurring. These antibodies are produced by the body's own immune system. Myasthenia gravis is an autoimmune disease because the immune systemwhich normally protects the body from foreign organisms mistakenly attacks itself. [2]

PATHOGENESIS
The fundamental disorder in myasthenia gravis is loss of functional acetylcholine receptors consequent upon binding of anti-acetylcholine receptor (anti-AChR) antibodies. In myasthenia gravis, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or "simplified." These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction. [1,2]

Figure IV : Adult onset autoimmune response The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electrodiagnostic testing. [3] Susceptibility to myasthenia gravis is associated with particular immune response genes, with correlation to different haplotypes relating to the age of onset of the disease. These observations are not of immediate relevance to routine clinical practice. In contrast, knowledge about involvement of the thymus is relevant to classification and management. 10

The neuromuscular abnormalities in myasthenia gravis are brought about by an autoimmune response mediated by specific anti-AChR antibodies. Loss of functional acetylcholine receptors by antibody binding is due to complement-mediated lysis, acceleration of internalization and degradation, and blocking of acetylcholine binding. The anti-AChR antibodies reduce the number of available AChRs at neuromuscular junctions by three distinct mechanisms: (1) accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) blockade of the active site of the AChR, i.e., the site that normally bindsACh; and (3) damage to the postsynaptic muscle membrane by the antibody in collaboration with complement. The pathogenic antibodies are IgG and are T cell dependent. Thus, immunotherapeutic strategies directed against T cells are effective in this antibody-mediated disease. [2,3] Morphological consequences include widening of the synaptic cleft and a marked reduction of the postsynaptic folds of the muscle fibre membrane. How the autoimmune response is initiated and maintained inMG is not completely understood. However, the thymus appears to play a role in this process. The thymus is abnormal in 75% of patients with MG; in about 65% the thymus is "hyperplastic," with the presence of active germinal centers, while 10% of patients have thymic tumors (thymomas). Muscle-like cells within the thymus (myoid cells), which bearAChRs on their surface, may serve as a source of autoantigen and trigger the autoimmune reaction within the thymus gland. In early-onset, seropositive patients there is hyperplasia of the thymic medulla, with germinal centres surrounded by a T-cell zone. The acetylcholine receptor is expressed on thymic myoid cells and there is enrichment of acetylcholine receptor-specific T cells. In addition, the thymus has a key role in the process of inducing immune tolerance, by removal of self-antigen T-cell clones. On the basis of these observations, and the beneficial response to thymectomy, there seems little doubt that the thymus is involved in the pathogenesis of myasthenia gravis, but exactly how has yet to be elucidated. Identification of the mechanism may well be important in developing immune-specific treatment. In late-onset cases and seronegative patients, the thymus is typically normal or atrophic, although some pathological changes have been noted.

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CLINICAL FINDINGS
The symptoms of MG have three general characteristics that, together, provide a diagnostic combination. Formal diagnosis depends on demonstration of the response to cholinergic drugs, electrophysiologic evidence of abnormal neuromuscular transmission, and demonstration of circulating antibodies to AChR. [1]

The fluctuating nature of myasthenic weakness is unlike any other disease. The weakness varies in the course of a single day, sometimes within minutes, and it varies from day to day or over longer periods. Major prolonged variations are termed remissions or exacerbations ; when an exacerbation involves respiratory muscles to the point of inadequate ventilation, it is called a crisis. Variations sometimes seem related to exercise; this and the nature of the physiologic abnormality have long been termed excessive fatigability but there are practical reasons to de-emphasize fatigability as a central characteristic of MG. Patients with the disease almost never complain of fatigue or symptoms that might be construed as fatigue except when there is incipient respiratory muscle weakness. Myasthenic symptoms are always owing to weakness and not to rapid tiring. In contrast, patients who complain of fatigue, if they are not anemic or harboring a malignant tumor, almost always have emotional problems, usually depression. [2]

Figure V : A drooping eyelid, or ptosis, is the most frequent early sign of myasthenia gravis, a disease that produces extensive muscle weakness. (Illustrations by Kathryn Born) The second characteristic of MG is the distribution of weakness. Ocular muscles are affected first in about 40% of patients and are ultimately involved in about 85%. Ptosis and diplopia are the symptoms that result. Other common symptoms affect facial or oropharyngeal muscles, resulting in 12

dysarthria, dysphagia, and limitation of facial movements. Together, oropharyngeal and ocular weakness cause symptoms in virtually all patients with acquired MG. Limb and neck weakness is also common, but in conjunction with cranial weakness. Almost never are the limbs affected alone. [2,3]

Figure VI : One of the Myasthenia Gravis manifestation

Crisis is most likely to occur in patients with oropharyngeal or respiratory muscle weakness. It seems to be provoked by respiratory infection in many patients or by surgical procedures, including thymectomy, although it may occur with no apparent provocation. Both emotional stress and systemic illness may aggravate myasthenic weakness for reasons that are not clear ; in patients with oropharyngeal weakness, aspiration of secretions may occlude lung passages to cause rather abrupt onset of respiratory difficulty. Major surgery may be followed by respiratory weakness without aspiration, however, so this cannot be the entire explanation. Spontaneous crisis seems to be less common now than it once was. [3]

The third characteristic of myasthenic weakness is the clinical response to cholinergic drugs. This occurs so uniformly that it has become part of the definition, but it may be difficult to demonstrate in some patients, especially those with purely ocular myasthenia.

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Figure VII : Immune system attack on the receptors for acetylcholine, the neurotransmitter that commands muscles to move. About three quarters of all people with myasthenia have abnormalities of the thymus gland, which is suspected of being the source of the immune systems error. Aside from the fluctuating nature of the weakness, MG is not a steadily progressive disease. The general nature of the disease, however, is usually established within weeks or months after the first symptoms. If myasthenia is restricted to ocular muscles for 2 years, certainly if it is restricted after 3 years, it is likely to remain restricted, and only in rare cases does it then become generalized. Distinguishing solely ocular myasthenia from generalized myasthenia soon after onset is challenging. Solely ocular myasthenia differs serologically from generalized myasthenia because AChR antibodies are found in lower frequency 50% and in low titer. Additionally, single-fiber EMG is more likely to be normal. Current debate centers on ability to predict generalized spread after ocular onset. Some suggest that early immunosuppressant will suppress/retard generalization. However, there have been no reports of successful weaning from these medications followed by complete remission. Spontaneous remissions occur in about 25% of all patients and are also more likely to occur in the first 2 years. [2,3]

Before the advent of intensive care units and the introduction of positive pressure respirators in the 1960s, crisis was a life-threatening event, and the mortality of the disease was about 33%. With improved respiratory care, however, patients rarely die of MG, except when cardiac, renal, or other disease complicates the picture. 14

The next most frequent presentation is with limb-girdle weakness. The limb weakness in myasthenia gravis is often proximal and may be asymmetric. Despite the muscle weakness, deep tendon reflexes are preserved. [1,2] However, there are many variations on this theme. A relatively common presentation in older patients, typically men, is with selective weakness of neck extensionas they walk their head drops forwards and they arrive in the clinic holding up their head with a hand under the chin. Relatively selective weakness of finger extension and abduction is common. Respiratory muscle weakness may be out of proportion to limb weaknessit is best assessed by measuring the vital capacity (not peak flow), and the effects of it by monitoring oxygen saturation. If weakness of respiration becomes so severe as to require respiratory assistance, the patient is said to be in crisis.

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DIAGNOSIS
The diagnosis is suspected on the basis of weakness and fatigability in the typical distribution described above, without loss of reflexes or impairment of sensation or other neurologic function. The suspected diagnosis should always be confirmed definitively before treatment is undertaken : this is essential because (1) other treatable conditions may closely resemble MG and (2) the treatment of MG may involve surgery and the prolonged use of drugs with adverse side effects. [2] Anticholinesterase Test Drugs that inhibit the enzyme AChE allow ACh to interact repeatedly with the limited number of AChRs, producing improvement in the strength of myasthenic muscles. Edrophonium is used most commonly, because of the rapid onset (30 s) and short duration (about 5 min) of its effect. An objective end-point must be selected to evaluate the effect of edrophonium. The examiner should focus on one or more unequivocally weak muscle groups and evaluate their strength objectively. For example, weakness of extraocular muscles, impairment of speech, or the length of time that the patient can maintain the arms in forward abduction may be useful measures. An initial dose of 2 mg of edrophonium is given intravenously. If definite improvement occurs, the test is considered positive and is terminated. If there is no change, the patient is given an additional 8 mg intravenously. The dose is administered in two parts because some patients react to edrophonium with unpleasant side effects such as nausea, diarrhea, salivation, fasciculations, and rarely syncope or bradycardia. Atropine (0.6 mg) should be drawn up in a syringe, ready for intravenous administration if these symptoms become troublesome. [2] False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral sclerosis, and in placebo-reactors. False-negative or equivocal tests also may occur. In some cases it is helpful to use a longer-acting drug such as Neostigmine (15 mg given orally), since this permits more time for detailed evaluation of strength. In virtually all instances, it is desirable to carry out further testing to establish the diagnosis of MG definitively. Electrodiagnostic Testing Repetitive nerve stimulation often provides helpful diagnostic evidence of myasthenia gravis. Anti-AChE medication is stopped 6 to 24 h before testing. It is best to test weak muscles or proximal muscle groups. Electric shocks are delivered at a rate of two or three per second to the appropriate nerves, and action potentials are recorded from the muscles. In normal individuals, the amplitude of the evoked muscle action potentials does not change at these rates of stimulation. However, in myasthenic patients there is a rapid reduction in the amplitude of the evoked responses of more than 10 to 15%. As a further test, a single dose of Edrophonium may be given to prevent or diminish this decremental reaction. [3] 16

Antiacetylcholine Receptor Antibody As noted above, anti-AChR antibodies are detectable in the serum of approximately 80% of all myasthenic patients, but in only about 50% of patients with weakness confined to the ocular muscles. The presence of anti-AChR antibodies is virtually diagnostic of myasthenia gravis, but a negative test does not exclude the disease. The measured level of anti-AChR antibody does not correspond well with the severity of myasthenia gravis in different patients. However, in an individual patient, a treatment-induced fall in the antibody level often correlates with clinical improvement. The congenital myasthenic syndromes (CMS) comprise a heterogeneous group of disorders of the neuromuscular junction that are not autoimmune, but rather are due to genetic mutations in which virtually any component of the neuromuscular junction may be affected. Alterations in function of the presynaptic nerve terminal, the various subunits of the AChR or AChE have been identified in the various forms of CMS. These disorders share many of the clinical features of autoimmune myasthenia gravis, including weakness and fatigability of skeletal muscles, in some cases involving extraocular muscles (EOMs), lids, and proximal muscles, similar to the distribution in autoimmune myasthenia gravis. CMS should be suspected when symptoms of myasthenia have begun in infancy or childhood, and AChR antibody tests are consistently negative. [2] Routine examinations of blood, urine, and CSF are normal. The characteristic electrodiagnostic abnormality is progressive decrement in the amplitude of muscle action potentials evoked by repetitive nerve stimulation at 3 or 5 Hz. In generalized MG, the decremental response can be demonstrated in about 90% of patients, if at least three neuromuscular systems are used (medianthenar, ulnar-hypothenar, accessory-trapezius). In microelectrode study of intercostal muscle, the amplitude of miniature end plate potentials is reduced to about 20% of normal. This is caused by a decrease in the number of AChR available to agonists applied by microiontophoresis.

In single-fiber EMG, a small electrode measures the interval between evoked potentials of the muscle fibers in the same motor unit. This interval normally varies, a phenomenon called jitter, and the normal temporal limits of jitter have been defined. In MG, the jitter is increased, and an impulse may not appear at the expected time; this is called blocking, and the number of blockings is increased in myasthenic muscle. All these electrophysiologic abnormalities are characteristic of MG, but blocking and jitter are also seen in disorders of ACh release. The standard EMG is usually normal, occasionally shows a myopathic pattern, and almost never shows signs of denervation unless some other condition supervenes. Similarly, nerve conduction velocities are normal. [3]

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DIFFERENTIAL DIAGNOSIS
There are few difficulties in the presence of extraocular muscle involvement and readily demonstrable fatigue, although there can be confusion with the LambertEaton myasthenic syndrome and the congenital myasthenic syndromes. Diagnostic difficulties can occur when, as occasionally happens, eye signs and fatigue are absent. Amyotrophic lateral sclerosis with little wasting may be suspected. Conversely, in long-established myasthenia, muscle wasting may be misleading. More difficult is seronegative, purely ocular myastheniathe most important differential diagnosis is mitochondrial cytopathy, in which increased jitter may also occur. Other diagnoses to consider include oculopharyngeal muscular dystrophy and thyroid ophthalmopathy. [1,2] Botulism, caused by food poisoning, an infected wound, or clostridial overgrowth in the gastrointestinal tract in infants, may need to be considered. Features of autonomic malfunction are usually present. [1] The only other conditions in which clinical improvement has been documented after use of edrophonium are other disorders of neuromuscular transmission: botulinum intoxication, snake bite, organophosphate intoxication, or unusual disorders that include features of both MG and the Lambert-Eaton syndrome. Denervating disorders, such as motor neuron disease or peripheral neuropathy, do not show a reproducible or unequivocal clinical response to edrophonium or neostigmine. The response should be unequivocal and reproducible. If a structural lesion of the third cranial nerve seems to respond, the result should be photographed.

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TREATMENTS
Thymectomy As noted, thymomas require excision, but this in itself will not improve the myasthenia. For thymectomy, two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for myasthenia gravis. Surgical removal of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are benign. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, 35% achieve drug-free remission. However, the improvement is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long-term benefit, in some cases diminishing or eliminating the need for continuing medical treatment. In view of these potential benefits and of the negligible risk in skilled hands, thymectomy has gained widespread acceptance in the treatment of myasthenia gravis. It is the consensus that thymectomy should be carried out in all patients with generalized myasthenia gravis who are between the ages of puberty and at least 55 years. Whether thymectomy should be recommended in children, in adults >55 years of age, and in patients with weakness limited to the ocular muscles is still a matter of debate. Thymectomy must be carried out in a hospital where it is performed regularly and where the staff is experienced in the pre- and postoperative management, anesthesia, and surgical techniques of total thymectomy. [2] Anticholinesterase Drugs Anticholinesterase drugs, by reducing acetylcholine breakdown, give symptomatic improvement in most patients, and may be sufficient in those with very mild disease. Pyridostigmine is the drug of choice, given orally four or five times daily, starting at 30 mg per dose and increasing if required to 60 mg. Abdominal cramping is a common side-effect, relating to muscarinic overstimulation, and responds to propantheline, ideally taken 30 min before each dose of pyridostigmine. If an adequate response is not obtained at this dose, then further increases should not be made and other forms of therapy should be considered. The management of ocular myasthenia differs somewhat from the generalized form of the disease, the latter also depending upon age of onset and antibody status. [1] Corticosteroids If anticholinesterase drugs have given an inadequate response, alternate-day prednisolone therapy should be introduced. A suitable starting daily dose is 5 mg, increasing by 5 mg every fourth dose (or weekly) until an adequate response has been obtained (often, for an adult, a dose of around 30 mg) 19

or a maximum acceptable dose (around 0.75 mg/kg body weight) has been reached. Once remission has been achieved, the pyridostigmine can be withdrawn, and then the prednisolone reduced slowly initially by 5 mg per month, but when down to 20 mg by as little as 1 mg, each month). Azathioprine may be added if there is an inadequate response or the minimal effective dose of prednisolone is deemed to be unacceptably high. Ocular muscle surgery can be beneficial if there is a poor or incomplete response to treatment and if the defect appears to be fixed. [1,3] Early-onset, seropositive myasthenia Many, but not all, of these patients benefit from thymectomy. Up to one-third enter remission, and a further one-half improve. These benefits are occasionally rapid, but more typically develop over the following 1 to 2 years, possibly longer. The conventional approach is through a sternal split. There is concern that less invasive surgical procedures risk leaving behind thymic remnants which will negate the benefits of the operation. Thymectomy should be performed in centres experienced in such surgery and with the support of appropriately trained anaesthetists and neurologists. [1,2] For those patients who do not respond adequately to anticholinesterase drugs and thymectomy, immunosuppression with prednisolone and azathioprine is indicated. A controlled trial has shown the benefits of the addition of azathioprine (2.5 mg/kg body weight per day)the starting dose is 25 or 50 mg daily, increased by 25 or 50 mg daily, each week (or more rapidly as an in-patient) until the target dose is reached. During introduction, weekly tests of full blood count and liver function are required. When established, testing can be reduced gradually to 3-monthly. Introduction of prednisolone may exacerbate myasthenic weakness and should generally be done in hospital. The starting dose is 10 mg on alternate days, increasing by 10 mg per dose until the patient reaches the target dose of 1 to 1.5 mg/kg body weight per dose. When remission has been achieved the dose is slowly reduced, as for ocular myasthenia, until the minimal effective dose has been established. [1] For those who do not respond to, or are intolerant of, prednisolone and/or azathioprine, other immunosuppressant drugs such as cyclosporin, methotrexate, or cyclophosphamide may be used. Late-onset and seronegative myasthenia Although not formally assessed, it appears that these patients do not benefit significantly from thymectomy. Most respond to the immunosuppressant regime described above. [1] Myasthenic crisis Intubation and assisted ventilation may be required. Plasma exchange and intravenous immunoglobulin may both lead to a rapid improvement (within 1 to 2 weeks) in strength, but the 20

beneficial effects start to wear off within about 8 weeks. However, this gives useful time in which to establish an immunosuppressant regime, as discussed above. [1,2] Plasma exchange and intravenous immunoglobulin are also useful in preparing myasthenic patients for thymectomy and may reduce the likelihood of deterioration consequent upon the introduction of prednisolone. Osteoporosis is an important concern in patients receiving long-term, high-dose prednisolone. Bone density determination should be carried out before starting such therapy, and repeated periodically, as appropriate. Local guidelines should be followedthese will advise on general physical measures, assess dietary calcium intake, and indicate the need to introduce calcium/vitamin D or a bisphosphonate, and the place of hormone replacement therapy for postmenopausal women. [1]

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PROGNOSIS
The outlook for most patients with myasthenia is good, with over 90 per cent achieving near-normal functional recovery. Death is most likely to occur during a myasthenic crisis early in the course of the disease. The response to thymectomy has been noted. Unwanted effects relating to the immunosuppressant drugs may have an important influence on the outcome.

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CHAPTER III CONCLUSION

Myasthenia Gravis is a common disease. An apparent increase in the incidence of the disease in recent years is probably owing to improved diagnosis. According to Phillips and Torner (1996), the prevalence rate is 14 per 100,000 (or about 17,000 cases) in the United States. Before age 40 years, the disease is three times more common in women, but at older ages both sexes are equally affected. [1] Myasthenia gravis is caused by a defect in the transmission of nerve impulses to muscles. It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junctionthe place where nerve cells connect with the muscles they control. The first steps of diagnosing myasthenia gravis include a review of the individual's medical history, and physical and neurological examinations. The physician looks for impairment of eye movements or muscle weakness without any changes in the individual's ability to feel things. If the doctor suspects myasthenia gravis, several tests are available to confirm the diagnosis. There are several therapies available to help reduce and improve muscle weakness. Medications used to treat the disorder include anticholinesterase agents such as neostigmine and pyridostigmine, which help improve neuromuscular transmission and increase muscle strength. Immunosuppressive drugs such as prednisone, azathioprine, cyclosporin, mycophenolate mofetil, and tacrolimus may also be used. [2] Thymectomy is recommended for individuals with thymoma. Other therapies used to treat myasthenia gravis include plasmapheresis, a procedure in which serum containing the abnormal antibodies is removed from the blood while cells are replaced, and high-dose intravenous immune globulin, which temporarily modifies the immune system by infusing antibodies from donated blood.

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CHAPTER IV REFERENCES
1. Jones, Hilton D. Disorders of the neuromuscular junction. Oxford textbook of medicine. Page 573. 2. Drachman DB. Myasthenia gravis and other diseases of the neuromuscular junction. Harrison's principles of internal medicine 16th edition 2005. Page 2581. 3. Aminoff, Greenberg et al. Disorders of neuromuscular transmission. Langes clinical neurology 6th edition page 183 186.

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