Clin Drug Investig 2011; 31 (1): 1-14 1173-2563/11/0001-0001/$49.95/0

REVIEW ARTICLE

ª 2011 Adis Data Information BV. All rights reserved.

Diagnosis and Management of Autoimmune Myasthenia Gravis Corrado Angelini Department of Neurosciences, University of Padova, Padova, Italy and IRCSS S. Camillo, Venice, Italy

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1 Burden of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3. Pathophysiology and Clinical Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4. Diagnosis and Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.1 Diagnostic Work-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1.1 Pharmacological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1.2 Serological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1.3 Electrophysiological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.1.4 Imaging Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.2 Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 5.1 Acetylcholinesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 5.1.1 Pyridostigmine (Bromide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.1.2 Neostigmine (Bromide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.1.3 Ambenonium (Chloride). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.2 Long-Term Immunotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.2.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.2.2 Immunomodulatory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.3 Short-Term Immunotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 5.4 Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 5.5 Anti-Sense Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 5.6 Surgical Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Abstract

Earlier diagnosis and the availability of effective treatments have reduced the burden of high mortality and severe disability previously associated with myasthenia gravis (MG). Consequently, the prognosis of MG is now much improved. However, despite extensive knowledge of MG and its aetiology, diagnosing the disease remains problematic and can be delayed because of its nonspecific and fluctuating symptoms, and the management of MG is associated with considerable limitations. Current treatments based on immunomodulation are associated with adverse effects arising from prolonged immune suppression. There is a need for improved awareness among primary caregivers about this relatively rare, but treatable, disease.

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1. Introduction The neuromuscular junction (NMJ) is the communication synapse between nerve and muscle at which an electrical nerve impulse is translated into an electrical stimulation to initiate muscle contraction.[1] Acetylcholine (ACh) acts as the chemical messenger across the synaptic cleft between nerve fibre endings and postsynaptic muscle membrane.[2,3] ACh is released into the synaptic cleft on nerve depolarization and rapidly diffuses across the gap to bind to ACh receptors (AChRs) clustered in high density in the endplate region opposite the release point.[4] AChRs can be either nicotinic or muscarinic. The nicotinic AChR, found primarily at the neuromuscular junction, is a multimeric protein comprised in adults of two a subunits and one each of b, d and e subunits. Each a subunit has a binding site for ACh. Muscle-specific tyrosine kinase (MuSK) is an AChR-associated protein involved in clustering of AChRs during synapse formation and is expressed in the mature NMJ.[5,6] In healthy individuals, binding of ACh to its receptor results in the generation of an action potential necessary for muscle contraction. Autoimmune disorders result from the loss of tolerance to self-antigens, such that a specific humoral (antibody-mediated) or cell-mediated immune response is raised against constituents of the body’s own tissues. In the case of myasthenia gravis (MG), an autoimmune disorder characterized by clinical fatiguable weakness, the body mounts an autoimmune attack on its own muscle endplate, initiated by antibody binding to AChR a subunits or, less frequently, to MuSK, resulting in abnormal neuromuscular transmission and muscle weakness. In this review, we present a summary of current knowledge on the epidemiology, pathophysiology, diagnosis and management of autoimmune MG. Non-systematic MEDLINE searches using the search terms ‘myasthenia gravis’ and ‘autoimmune’ were performed and appropriate citations were manually selected from the search results for inclusion in this review. A similar group of neuromuscular disorders, congenital myasthenic syndromes, is caused by genetic mutations resulting in abnormal neuromuscular transmission,[7] and is not discussed further in this review. ª 2011 Adis Data Information BV. All rights reserved.

2. Epidemiology MG used to be considered a very rare disease; however, incidence and prevalence rates have increased over time, as a result of an aging population, increased incidence from improved diagnosis, and prolonged survival with the disease.[8] Nevertheless, MG is still relatively rare, with current incidence estimates ranging from 9 to 21 per million population and prevalence rates estimated at 50–125 cases per million population worldwide,[4] increasing to as high as 200 per million population in some Western countries such as the US.[9] The onset and incidence of MG are influenced by age and sex, and MG was first thought to be a condition of the young. It is now known that women have a peak onset at around 20-40 years of age, whereas men have two peaks, one in the third decade and another in the sixth decade.[9,10] MG may be under-diagnosed in the elderly,[11] and incidence rates may be as high as 60 per million in this population.[12-14] In a 10-year prospective study in a relatively stable population in the Barcelona province of Spain, the overall annual incidence rate was 21.27 per million inhabitants and the incidence in those aged ‡65 years was significantly higher (p < 0.0001) than in younger patients at 63.4 per million inhabitants.[13] A similar increased incidence due to aging was seen in both men and women, although in this study the overall incidence rate and the rates for each age group were higher for women than for men.[13] 2.1 Burden of Disease

Prior to the widespread use of immunomodulatory drugs, the prognosis for patients with MG was poor, with approximately 30% mortality, mostly within the first few years following diagnosis.[15,16] Improvements in diagnosis and treatment have contributed to a current disease-specific mortality of less than 5%.[11,16,17] Despite advances in treatment and improved clinical outcomes, many patients do not achieve full remission and go on to experience chronic symptoms and disability; however, due to the lack of large randomized controlled trials, the actual proportion of patients who remain symptomatic on treatment and the actual levels of disability are not clear. Clin Drug Investig 2011; 31 (1)

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As with any chronic disease, the effects of MG on quality of life (QOL) are significant. These may extend beyond the impact on physical aspects of QOL related to the disease itself to the adverse effects of chronic immunosuppressant drug therapy. Psychological effects on QOL also include those related to the medication and to the disease; treatment may not produce completely stable remission, which can cause significant anxiety,[18] and there are disease- and treatment-related adverse effects that can affect body image and mental state.[19] The quantitative MG (QMG) assessment scale has been developed to objectively evaluate clinical change in MG treatment trials.[20,21] The Short-Form 36 Health Survey (SF-36)[22] has been widely used to assess QOL in patients with MG. More recently, an MG-specific questionnaire, MG-QOL, was developed with better performance versus SF-36 in demonstrating disease change assessed by the QMG.[23,24] Early studies of QOL using non-MG-specific instruments did not show a large impact on mental aspects of QOL, although physical aspects were progressively impacted by disease severity.[25-27] However, the impact of MG on mental and psychiatric well-being should not be underestimated,[18] particularly in cases with bulbar or generalized involvement.[28] The additional burden of psychiatric disorders can be substantial, presenting mainly as anxiety and depressive disorders.[18] Psychiatric disturbances were observed in 51% of MG cases: adjustment disorders with depressed mood, anxiety and mixed emotional features in 22%, personality disorders in 18% and affective disorders in 13.5%.[29] The 60-item disease-specific MG-QOL scale for assessment of both the physical and psychological aspects of QOL in MG correlated more closely with QMG score than SF-36; both the physical and psychological aspects of QOL correlated with the QMG score, but the associations were stronger with physical than with psychological aspects.[24] Recently a simplified and more easily administered 15-item MG-QOL scale was found to have similar correlation to the 60-item MG-QOL with QMG, MG-specific Manual Muscle Testing (MG-MMT), and the MG-specific ª 2011 Adis Data Information BV. All rights reserved.

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Activities of Daily Living (MG-ADL) scores, and was shown to have high sensitivity.[23] Patients with MG also have an increased risk of other diseases of the thyroid gland (one study reported hypothyroidism in 3% and hyperthyroidism in 3% of patients with MG[30]) and other autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.[4]

3. Pathophysiology and Clinical Course MG is perhaps the best understood of all the autoimmune diseases. Seropositive MG is characterized by the presence of antibodies to AChRs, and approximately 80% of patients with generalized MG are seropositive.[31,32] AChR antibodies can produce defects in neuromuscular transmission via a number of different mechanisms: by binding to AChRs and affecting their function; by binding and cross-linking AChRs, leading to increased degradation rate and lower AChR density; and by directing complement-mediated damage to the postsynaptic endplate.[2] The last mechanism is considered the most important. Complement attack results in physical damage to the muscle endplate, loss of AChR-rich membrane (figure 1) and the generation of inflammatory mediators.[2,3] A study of 150 AChR-antibody-seronegative MG patients from several centres identified antibodies to MuSK in 41%.[33] The presence of MuSK antibodies in seronegative MG appears to correlate with a higher rate of a more severe ocular-bulbar variant of MG, and most patients with this form of MG require immunosuppressant treatment.[34] However, the incidence of MuSK-antibody-positive MG varies among published reports and the mechanisms involving MuSK antibodies in producing disease at the mature NMJ have not yet been fully elucidated.[35] Muscle biopsies have shown histopathological differences between patients with AChRantibody-positive and MuSK-antibody-positive MG: neurogenic features and atrophy are more common in patients with AChR-antibody-positive MG, while patients with MuSK-antibody-positive MG show myopathic signs with prominent mitochondrial abnormalities.[36,37] The association between Clin Drug Investig 2011; 31 (1)

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a Normal Axon Mitochondrion

Vesicle

Release site Nerve terminal

Acetylcholine receptors Muscle Acetylcholinesterase b Myasthenia gravis

Fig. 1. Schematic representation of the neuromuscular junction (a) in normal individuals and (b) in patients with myasthenia gravis.[11] Note the widened synaptic cleft, reduced number of acetylcholine receptors and simplification of the postsynaptic membrane resulting from autoimmune attack in myasthenia gravis.

MuSK antibodies and mitochondria warrants further investigation. The thymus is a critical organ for T-cell education and elimination of auto-reactive T cells, and plays a major role in MG. Thymic abnormalities are frequently present in MG, including hyperplasia in about 65% of cases and thymoma in 10%.[17] It is thought that the expression of AChRs by myoid cells in the thymus, plus the inflammatory environment within the MG thymus, contribute ª 2011 Adis Data Information BV. All rights reserved.

to the induction and maintenance of the antiAChR autoimmune response.[38] Patients with MG present with weakness in specific muscle groups.[19,39] Initially, up to 65% of patients present with ocular symptoms, such as ptosis and diplopia, and about 25% present with bulbar weakness, resulting in slurred or nasal speech, voice alterations or difficulty in chewing or swallowing. Limb weakness is a less common initial complaint. Regardless of the muscles involved, the degree of weakness may vary from day to day, but, generally, the weakness is fatiguable, i.e. it worsens as the day progresses or because of sustained use of the affected muscles.[19,39] The progression of muscle weakness in MG usually occurs in a craniocaudal direction, i.e. beginning with ocular, facial and lower bulbar weakness and progressing to torso and limb muscle involvement. Maximal weakness occurs within the first year following symptom onset in approximately two-thirds of cases.[11] Very few patients progress from solely ocular to generalized MG after 2 years’ duration of disease, but the likelihood of remission is also seen to decrease gradually over time.[40] In a long-term follow-up study, Oosterhuis[15] reported that spontaneous remissions (defined as a clinical improvement without a change in therapy) and substantial improvement could occur after 2 years following onset, but that the clinical course varies greatly among individuals.

4. Diagnosis and Clinical Evaluation MG remains a challenging disease to diagnose due to its fluctuating character and to the similarity of symptoms to those of other disorders; the mean time to diagnosis is often over 1 year.[19,39] One study has shown that the mean time to diagnosis can be as long as 2 years, with patients frequently being initially misdiagnosed with mood and anxiety disorders.[18] Delayed diagnosis is a substantial clinical problem, since untreated patients are at risk of deterioration to the extent of myasthenic crisis. Myasthenic crisis is a life-threatening situation in which weakness of the respiratory muscles becomes sufficiently Clin Drug Investig 2011; 31 (1)

Autoimmune Myasthenia Gravis

severe to cause respiratory failure, requiring mechanical ventilation.[39] It is characterized by external eye signs due to weakness of ocular muscles (weakness in eye movement, normal and reactive pupils, ptosis), facial weakness, limb muscle weakness, and normal tendon and flexor plantar reflexes.[41] Drug treatment withdrawal and infections have been identified as risk factors for myasthenic crisis.[42] Evidence suggests that plasma exchange and intravenous immunoglobulin offer comparable efficacy in the treatment of myasthenic crisis,[43-46] but as response to plasma exchange is more predictable, this may be preferable to intravenous immunoglobulin in this setting.[41] Such is the aforementioned similarity between co-morbid psychiatric symptoms and MG symptoms that a psychiatric condition may mask MG symptoms and interfere with initial diagnosis. Conversely, co-morbid psychiatric symptoms that appear during the course of the illness may be misdiagnosed as myasthenic symptoms, leading to unnecessary or inappropriate drug treatment.[18] Diagnosis is further complicated by the fact that some myasthenic symptoms such as oropharyngeal symptoms may be thought to be due to intracranial pathology.[19] Unnecessary testing can be avoided if the diagnosis of MG is considered and confirmed early. 4.1 Diagnostic Work-Up

There is a range of physical and laboratory evaluations that can be applied to assess fatiguable weakness, ranging from the standard ice test and rest (or sleep) tests of improved ocular muscle function to more specialized assessments.[19,39,47] Specialized tests used to evaluate the physiological, electrophysiological and serological aspects of the disease are described below. The utility of 20 tests for the diagnosis of generalized and ocular MG have been evaluated and compared with the ice test and other commonly used evaluations in a systematic review.[48] The review concluded that, apart from AChR antibody testing and single-fibre electromyography (SFEMG), diagnostic tests were not adequately validated and, therefore, the results of these tests should be interpreted with caution.[48] ª 2011 Adis Data Information BV. All rights reserved.

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4.1.1 Pharmacological Testing

Edrophonium (chloride) is an acetylcholinesterase (AChE) inhibitor with rapid onset and short duration of action (personal observation). This agent is available as a solution for injection in the US, but not in all European countries. By inhibiting the degradation of ACh, edrophonium allows prolonged interaction of ACh with the reduced number of AChRs on the muscle endplate and consequently greater endplate depolarization (a sequence also known as the Tensilon test). MG muscle weakness typically improves with edrophonium treatment; however, this diagnostic test requires the patient to have easily assessed baseline weakness in specific muscles.[19,39] The edrophonium test is positive in 60-95% of patients with ocular MG and 72-95% of patients with generalized MG. Most affected muscles respond to edrophonium; however, the dose should be titrated. Adverse effects are rare and generally mild, although a low risk of serious adverse effects, such as bradycardia, asystole and bronchoconstriction, may necessitate cardiac monitoring and provision of standby ventilatory assistance facilities.[39] Edrophonium is not recommended for long-term treatment of MG because of its short duration of action (approximately 5 minutes).[39] Some patients who do not respond to edrophonium may respond to pyridostigmine (bromide) or neostigmine (bromide), both of which have a longer duration of action.[39] 4.1.2 Serological Testing

The assay for binding antibodies to AChRs is an essential diagnostic test for MG.[19] The test usually employs radiolabelled, purified AChRs from human skeletal muscle. Its sensitivity is reported as 50-75% for ocular MG and 70-95% for generalized MG.[19] Elevated antibody levels are found in 80% of those with generalized MG, but in only 55% of those with disease restricted to ocular weakness.[31,32] Normal antibody levels do not exclude a diagnosis of MG, however, and patients may present with seronegative disease. In seronegative MG patients, low/absent titres often increase with disease progression.[16] Interestingly, by incubating human embryonic kidney cells in sera from Clin Drug Investig 2011; 31 (1)

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patients with AChR-antibody-positive MG and seronegative MG, Vincent et al.[49] were able to detect low-affinity AChR antibodies in patients considered seronegative for AChR or MuSK antibodies. These antibodies were predominantly IgG1 and were shown to activate complement C3b deposition. These findings suggested that complement activation may be important, even in patients who do not possess conventional AChR antibodies.[49] Other anti-AChR antibody tests evaluate blocking or modulating antibodies, but these are of less diagnostic value.[19] As already highlighted in section 3, antibodies to MuSK have been detected in 41% of patients with seronegative MG.[33] There are isolated case reports of MuSK-antibody-positive ocular MG,[50] although, in general, patients with ocular MG do not have elevated antibodies to MuSK.[47] Anti-striated muscle antibodies are found in 30% of patients with adult-onset MG.[51] They react with contractile elements of skeletal muscle, but are not pathogenic for MG. In younger patients, anti-striated muscle antibodies may be an important marker for thymoma in the presence or absence of MG; they are usually seen in cases of late-onset MG with thymoma.[17,19,51] It should be noted, however, that these antibodies are of limited diagnostic value as they are also elevated in other disorders, including autoimmune liver disease, Lambert-Eaton syndrome and primary lung cancer.[19]

at some endplates fail; therefore, the compound muscle action potential is also reduced.[52] As with edrophonium testing, it is important to select an appropriate clinically weak muscle for testing.[53,54] Selection of muscle for RNS should be tailored to the clinical symptoms of the patient; an abnormal RNS diagnostic of MG is defined as a reproducible >10% decrease in amplitude between the first and the fourth or fifth stimulus in at least one muscle.[53] SFEMG is based on the principle that all muscle fibres in a motor unit are innervated by a single axon. The action potentials of individual muscle fibres are recorded and used to calculate neuromuscular jitter (the variation in time intervals between pairs of action potentials from two or more muscle fibres in a motor unit). SFEMG is the most sensitive diagnostic test in MG and should be performed if RNS is normal and an NMJ disorder is suspected.[19,53] However, it is a time-consuming test that requires special expertise and equipment not generally available outside academic centres.[55] In addition, abnormal results can be seen in neuronal and myopathic conditions.[19] SFEMG of at least one symptomatic muscle should be performed and, if normal and suspicion of NMJ disorder is high, another muscle should be tested. Abnormal SFEMG is defined as >10% of fibre potential pairs with higher than normal jitter or impulse blockade and/or mean jitter higher than normal.[53] Figure 2 shows a typical SFEMG re-

4.1.3 Electrophysiological Testing

Electrodiagnostic tests including repetitive nerve stimulation (RNS) and SFEMG are often required, particularly in seronegative MG and in patients in whom clinical assessments are ambiguous.[47] RNS depletes the immediate stores of ACh at the NMJ, which reduces the probability of successful neuromuscular transmission. In a normal individual, all endplate potentials are above the threshold for a muscle fibre’s active potential, and each muscle depolarization is therefore identical. However, in MG, RNS causes some endplate potentials to fail to reach depolarization threshold. Muscle fibre action potentials ª 2011 Adis Data Information BV. All rights reserved.

10ms 200μV

Fig. 2. Single-fibre electromyography recording in a patient with myasthenia gravis recorded during voluntary activation of the muscle. Consecutive discharges are superimposed. The sweep is triggered on the first potential, and increased jitter is seen in the second potential.[56]

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Table I. Myasthenia Gravis Foundation of America clinical classification of myasthenia gravis (reproduced with permission from Jaretzki et al.[21]) Class I

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

II

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

IIa

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

IIb

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

III

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

IIIa

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

IIIb

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

IV

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4.2 Clinical Evaluation

The Myasthenia Gravis Foundation of America (MGFA) recommendations for clinical research standards in MG include a classification system for clinical features and disease severity that may indicate different prognoses or responses to therapy.[21] The classification system is based on the affected muscle groups and on the degree of weakness (table I).[21] In conjunction with this system, a QMG assessment scale for disease severity was developed as an objective evaluation of response to treatment.[20,21] A recent composite evaluative instrument, the MG-Composite, based on individual items from the QMG, Manual Muscle Test and MGActivities of Daily Living scales, has been developed and is currently undergoing validation.[57,58] Initial studies show that the MG-Composite is quick and easy to administer and it is hoped that this instrument will provide a more accurate and responsive method of assessment of MG status and clinical change than other currently available instruments.[58]

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

IVa

Predominantly affecting limb and/or axial muscles May also have less involvement of oropharyngeal muscles

IVb

Predominantly affecting oropharyngeal muscles, respiratory muscles or both May also have lesser or equal involvement of limb muscles, axial muscles or both Use of a feeding tube without intubation

V

Requiring intubation, with or without mechanical ventilation, except when employed during routine postoperative management

cording from a patient with MG; neuromuscular jitter is evident after the second action potential.[56] SFEMG can be used as the initial NMJ test if the patient has very mild/ocular symptoms and RNS is likely to be normal, if RNS is not possible or painful, or if the local laboratory has strong SFEMG capability.[53] 4.1.4 Imaging Tests

Patients diagnosed with MG should have a chest imaging study (computed tomography or magnetic resonance imaging) to screen for possible thymoma or abnormal thymus gland.[19] ª 2011 Adis Data Information BV. All rights reserved.

5. Treatment The goals of treatment include control of muscle weakness and remission of MG. Current treatment options include AChE inhibitors, corticosteroids, immunosuppressants, immunotherapy (plasma exchange and intravenous immunoglobulins) and thymectomy, depending on the serological status of MG or presence of thymoma.[11,59] Treatment must be individualized to each patient and requires close medical supervision and long-term follow-up.[19] 5.1 Acetylcholinesterase Inhibitors

AChE inhibitors were among the earliest treatment options for MG. Physostigmine was the first AChE inhibitor to be used in MG. In 1934, Dr Mary Walker described the case of a patient with MG in whom muscle function was temporarily restored after treatment with subcutaneous physostigmine.[60] Physostigmine came to be replaced by neostigmine, which demonstrated a far more favourable safety profile than physostigmine and remained the primary agent used for Clin Drug Investig 2011; 31 (1)

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the treatment of MG until the introduction of pyridostigmine.[61] AChE inhibitors remain one of the most widely used treatment options and are also used in pharmacological diagnostic assessment as discussed in the Pharmacological Testing section.[19] European guidelines indicate that AChE inhibitors should be used as first-line treatment of MG.[62] Consequently, they are used as monotherapy for symptomatic treatment in most patients and as an adjunctive therapy in patients with more severe disease also receiving other treatment modalities.[19] AChE inhibitors slow the degradation of ACh at the NMJ, providing temporary improvement in muscle strength in many patients. However, they do not modify the underlying autoimmune disorder[63] and some patients are unresponsive to AChE inhibition.[19] AChE inhibitors are available in a range of formulations. Of these, the oral formulation of pyridostigmine bromide is the most commonly prescribed.[19] Common adverse effects are mainly due to cholinergic stimulation and arise from ACh accumulation at muscarinic AChRs on smooth muscle and autonomic glands. Cholinergic adverse effects, which include nausea, vomiting, abdominal cramps, diarrhoea, increased lacrimation, salivation and bronchial secretion, can be managed using anticholinergic medication without losing the desired nicotinic effect. Cholinergic crisis may develop as a result of very high AChE inhibitor dosing, which causes depolarization blockade at NMJs in affected muscles, resulting in increased muscle weakness.[19] Customization of AChE inhibitor dose to the individual is important to achieve the optimal therapeutic dose in terms of maximizing muscle strength and minimizing adverse effects and the risk of cholinergic crisis caused by overdosing. Dose titration (incremental dose increases and decreases) and alteration of treatment interval are often required during treatment initiation and throughout the treatment period; however, dose optimization can be difficult to achieve because of symptom fluctuation and the need for timeconsuming and complex clinical evaluation.[19] ª 2011 Adis Data Information BV. All rights reserved.

Dose optimization is further hindered by the wide variation in steady-state plasma concentrations of AChE inhibitors seen among individuals given the same ‘optimal’ dose.[64,65] In addition to edrophonium used for diagnosis of MG as described in the Pharmacological Testing section, the following AChE inhibitors are currently used in the treatment of MG. 5.1.1 Pyridostigmine (Bromide)

Pyridostigmine is a rapidly acting, reversible AChE inhibitor used extensively in the treatment of MG since 1952.[11] In addition to the standard oral formulation, pyridostigmine is also available as a sustained-release (SR) formulation in which the drug is released over 12 hours to simplify treatment and permit evening administration, thus ensuring that the patient remains symptom free throughout the night and on waking.[66-68] Pyridostigmine is the most widely used AChE inhibitor in MG,[4] being preferred to neostigmine because of its lower frequency of gastrointestinal adverse effects and longer duration of action.[19] Although there were many anecdotal reports of pyridostigmine use in MG after 1952, the pharmacology and clinical efficacy of pyridostigmine in improvement of muscle weakness in patients with MG was first demonstrated in an open-label trial only in 1987.[69] Pyridostigmine has been shown to have a longer duration of action in elderly than in younger patients[70] and a lower incidence of muscarinic adverse effects compared with neostigmine.[67] 5.1.2 Neostigmine (Bromide)

In Europe, neostigmine is available for parenteral and oral use.[71,72] The duration of action is shorter and the therapeutic index narrower with neostigmine than with pyridostigmine;[67] in addition, as with pyridostigmine, the duration of action of neostigmine is prolonged in the elderly.[70] Dose modification is required in the elderly and in patients with renal impairment.[71] 5.1.3 Ambenonium (Chloride)

Use of ambenonium (chloride) in MG was first described in 1955[73] and it is still in use today. Ambenonium has a longer duration of action than neostigmine, leading to a prolonged effect Clin Drug Investig 2011; 31 (1)

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through the night and on waking, and fewer gastrointestinal adverse effects. However, the longer duration of action also means that it must be used with caution in patients with asthma and Parkinson’s disease, in whom toxic effects could be life threatening, and ambenonium should not be used in combination with other AChE inhibitors.[74] 5.2 Long-Term Immunotherapy 5.2.1 Corticosteroids

Oral corticosteroids are widely used immunomodulatory agents for MG and are recommended as the drug of first choice when immunosuppression is required.[62] In a retrospective review of prednisone treatment in 116 consecutive patients with MG, more than 80% of patients achieved a marked improvement or complete relief of symptoms with prednisone therapy.[75] The effectiveness of corticosteroids in MG was also confirmed in a systematic Cochrane review.[76] Although the evidence is limited, significant short-term benefits in MG were seen with corticosteroids.[76] The most reliable clinical response to corticosteroids occurs with a high initial dose maintained until sustained improvement occurs (2-4 weeks), followed by a gradual dose decrease to the lowest dose that maintains improvement while reducing the risk of adverse effects.[19] Careful, individualized dose tapering is required. The adverse effects of corticosteroids are numerous and well documented. Approximately one-third of patients have temporary but potentially serious exacerbations after starting prednisone.[19] 5.2.2 Immunomodulatory Drugs

Several immunosuppressant drugs are used in the treatment of MG. However, the evidence for their use in MG is limited.[77] Azathioprine is the most frequently used for long-term immunomodulation in MG, but one study suggested benefits may not be apparent for up to 18 months after initiation of therapy.[78] In a 3-year, randomized, controlled, multicentre trial, one group received prednisolone on alternate days plus azathioprine (2.5 mg/kg), while the other group received prednisolone on alternate days plus placebo.[78] Prednisolone plus azathioprine combination therapy was shown to be effective when used as a corticosteroidª 2011 Adis Data Information BV. All rights reserved.

9

sparing agent, with a reduction in relapse and fewer treatment failures following prednisolone tapering, compared with prednisone plus placebo. The study showed that azathioprine could be used successfully to reduce the dose of prednisolone required to maintain remission. However, a recent Cochrane review stated that there was no clear evidence of benefit with any immunosuppressant drug commonly used in MG, including azathioprine given either as monotherapy or with corticosteroids.[79] Use of ciclosporin (cyclosporine) in MG is limited by its nephrotoxicity and numerous drug interactions; nevertheless, this drug may have benefit as a corticosteroid-sparing agent in patients with refractory MG.[19] Tindall et al.[80] reported that ciclosporin alone or in combination with corticosteroids may offer a significant benefit in MG compared with placebo; however, these are preliminary data and require confirmation. These findings are also supported by data from Bonifati and Angelini,[81] who showed that ciclosporin has a corticosteroid-sparing and plasma exchangesparing effect with minimal additional adverse effects in patients with severe MG. Cyclophosphamide, like azathioprine, inhibits lymphocyte proliferation. Cyclophosphamide has been used in severe, generalized MG that is refractory to corticosteroid treatment alone and, as with ciclosporin, has been shown in randomized, controlled trials to provide greater efficacy versus placebo when used as an add-on therapy with corticosteroids.[77] Mycophenolate mofetil is a newer immunomodulatory drug that has been studied recently for MG. Mycophenolate mofetil selectively inhibits the proliferation of activated B and T lymphocytes.[82] While a potential role for mycophenolate mofetil is recognized from case reports, retrospective series and pilot studies,[83] limited evidence from small randomized clinical trials shows no controlled benefit for mycophenolate mofetil as monotherapy or in combination with either corticosteroids or ciclosporin.[77,84] In a randomized trial of 80 patients with MG, the combination of mycophenolate mofetil plus prednisone yielded no additional benefit over prednisone alone.[85] However, a clinical benefit was demonstrated in a retrospective analysis of Clin Drug Investig 2011; 31 (1)

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>3 months’ mycophenolate mofetil treatment (with or without concomitant prednisone) in 103 patients with AChR-antibody-positive MG.[86] For tacrolimus, clinical benefits either with corticosteroids or with plasma exchange were not significantly greater than for placebo.[77] 5.3 Short-Term Immunotherapy

Plasma exchange and intravenous immunoglobulin therapy are two immune-related treatment options that have a rapid onset of effect but relatively short duration of action. Due to their rapid effect, these treatments are often used for patients with acute worsening of MG to improve strength prior to surgery, to prevent acute exacerbations induced by corticosteroids and as a chronic intermittent treatment to provide relief in patients with refractory MG.[19] Plasma exchange is based on the bulk removal of antibodies that contribute to the autoimmune condition and involves the removal of 2-3 L of plasma three times a week, repeated until the rate of improvement plateaus.[19] This approach has been shown to improve myasthenic weakness in nearly all patients and the effects can last up to 3 months.[87] Treatment with intravenous immunoglobulin involves the infusion of human polyclonal immunoglobulin. The precise mechanism of action is currently unclear; however, benefits have been reported in 50-100% of patients.[19] In a randomized, placebo-controlled study to determine the effectiveness of intravenous immunoglobulin in 51 patients with worsening weakness due to MG, a clinically meaningful improvement in disease severity was seen at 2 weeks and this persisted at 1 month.[46] Plasma exchange and intravenous immunoglobulin appear to be similarly effective in the short term;[88] however, there are no randomized controlled trials that assess the short- or longterm outcomes of plasma exchange in MG.[87] 5.4 Monoclonal Antibodies

Anecdotal evidence suggests B-cell-directed therapies may be of benefit in the treatment of MG. Anti-CD20 therapy was shown to be effective in a female patient with highly active MG.[89] ª 2011 Adis Data Information BV. All rights reserved.

Interestingly, in this patient, anti-AChR antibody titres remained high, suggesting either that the effect of anti-CD20 on MG occurred via an effect on cellular immune function, or that AChR antibody affinity and pathogenicity were modulated.[89] The efficacy of rituximab in MG has been reported in two case reports.[90,91] In the first, a 56-year-old woman with MuSK-antibodypositive MG improved after receiving rituximab therapy following failure of conventional immunosuppression to maintain clinical improvement.[90] Clinical improvement with rituximab correlated with a reduction in MuSK-antibody titre and was sustained for up to 12 months. In the second case report, the patient – a 21-year-old woman with seronegative MG – had also not responded to conventional immunosuppressant therapy but was reported to show dramatic improvement with rituximab.[91] On testing, this patient was also shown to be MuSK-antibody-positive,[91] suggesting that the seronegative MuSK-antibody-positive MG phenotype may have a better response to rituximab than to conventional therapy. 5.5 Anti-Sense Therapy

Anti-sense treatments are currently being investigated in several indications, including cancer, diabetes mellitus and MG. EN 101 (monarsen), an orally administered anti-sense oligonucleotide treatment, has been shown to reduce production of AChE by blocking the conversion of RNA into the AChE protein.[92] In a phase Ib study in patients with MG, EN 101 improved muscle strength (as indicated by a reduction in QMG score) in 14 of the 16 patients examined.[92] EN 101 is currently in phase II clinical development for the treatment of MG in the UK. 5.6 Surgical Treatment Options

Studies of thymectomy in patients with nonthymomatous autoimmune MG are limited and cannot show definitively whether the observed association between thymectomy and improved outcomes was due to the thymectomy or was merely a result of variation in baseline characteristics between the surgical and nonsurgical groups.[93] Thus, for patients with non-thymomatous autoClin Drug Investig 2011; 31 (1)

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immune MG, thymectomy is recommended as an option only to increase the likelihood of clinical improvement or remission.[94] Patients with seronegative MG have also been shown to benefit from thymectomy.[19] The best improvements are generally seen in younger patients;[95] however, similar outcomes in older and younger patients have also been reported.[96] One study showed a substantially higher rate of improvement but a lower remission rate in patients aged >60 years undergoing thymectomy compared with younger patients.[97] Currently, the role for thymectomy in non-thymomatous MG with purely ocular involvement remains uncertain, as does that in seronegative MG patients with MuSK antibodies;[19,98,99] however, a retrospective chart review of 53 MuSK-antibody-positive patients with MG showed that thymectomy was beneficial in 7/18 patients at 3 years.[100] An ongoing international phase III clinical trial in non-thymomatous MG patients is investigating whether thymectomy plus prednisone therapy is more effective than prednisone alone.[101] Once thymoma is diagnosed, thymectomy is indicated irrespective of severity of MG.[62] 6. Conclusions MG was previously associated with a high mortality rate and severe disability. Earlier diagnosis and the availability of effective treatments have reduced this burden, such that the prognosis of MG is now much improved. However, work still needs to be done, as many people do not achieve full remission. Diagnosis of MG remains problematic due to nonspecific and fluctuating symptoms, with diagnosis taking up to 2 years in some cases, and patients frequently being initially misdiagnosed as having neurotic disorders. Current treatments must be tailored to the individual. Treatment modalities based on immunomodulation are associated with adverse effects arising from prolonged immune suppression. There is a need to educate and improve awareness among primary caregivers about this rare, but eminently treatable, disease. Acknowledgements The author thanks Rod McNab and Mary Hines from inScience Communications, a Wolters Kluwer business, who

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provided medical writing services funded by MEDA Group, Spain. The author also acknowledges the supportive discussions at Eurobiobank (supported by Translational Research in Europe – Assessment and Treatment of Neuromuscular Diseases [TREAT-NMD]) and the support of the Italian Ministry of Education. The author has no conflicts of interest that are directly relevant to the content of this review.

References 1. Tiedt TN, Albuquerque EX, Hudson CS, et al. Neostigmineinduced alterations at the mammalian neuromuscular junction. I. Muscle contraction and electrophysiology. J Pharmacol Exp Ther 1978 May; 205 (2): 326-39 2. Boonyapisit K, Kaminski HJ, Ruff RL. Disorders of neuromuscular junction ion channels. Am J Med 1999 Jan; 106 (1): 97-113 3. Hughes BW, Kusner LL, Kaminski HJ. Molecular architecture of the neuromuscular junction. Muscle Nerve 2006 Apr; 33 (4): 445-61 4. Drachman DB. Myasthenia gravis. N Engl J Med 1994 Jun 23; 330 (25): 1797-810 5. Hoch W, McConville J, Helms S, et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001 Mar; 7 (3): 365-8 6. Witzemann V. Development of the neuromuscular junction. Cell Tissue Res 2006 Nov; 326 (2): 263-71 7. Harper CM. Congenital myasthenic syndromes. Semin Neurol 2004 Mar; 24 (1): 111-23 8. Phillips 2nd LH, Torner JC. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology 1996 Nov; 47 (5): 1233-8 9. Phillips 2nd LH. The epidemiology of myasthenia gravis. Ann N Y Acad Sci 2003 Sep; 998: 407-12 10. Flachenecker P. Epidemiology of neuroimmunological diseases. J Neurol 2006 Sep; 253 Suppl. 5: V2-8 11. Thanvi BR, Lo TC. Update on myasthenia gravis. Postgrad Med J 2004 Dec; 80 (950): 690-700 12. Aarli JA. Myasthenia gravis in the elderly: is it different? Ann N Y Acad Sci 2008; 1132: 238-43 13. Aragones JM, Bolibar I, Bonfill X, et al. Myasthenia gravis: a higher than expected incidence in the elderly. Neurology 2003 Mar 25; 60 (6): 1024-6 14. Vincent A, Clover L, Buckley C, et al. Evidence of underdiagnosis of myasthenia gravis in older people. J Neurol Neurosurg Psychiatry 2003 Aug; 74 (8): 1105-8 15. Oosterhuis HJ. The natural course of myasthenia gravis: a long term follow up study. J Neurol Neurosurg Psychiatry 1989 Oct; 52 (10): 1121-7 16. Grob D, Brunner N, Namba T, et al. Lifetime course of myasthenia gravis. Muscle Nerve 2008 Feb; 37 (2): 141-9 17. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis 2007; 2: 44 18. Kulaksizoglu IB. Mood and anxiety disorders in patients with myasthenia gravis: aetiology, diagnosis and treatment. CNS Drugs 2007; 21 (6): 473-81 19. Myasthenia Gravis Foundation of America. Myasthenia gravis: a manual for the health care provider [online].

Clin Drug Investig 2011; 31 (1)

Angelini

12

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

Available from URL: http: //www.myasthenia.org/docs/ MGFA_ProfessionalManual.pdf [Accessed 2008 Nov 18] Barohn RJ, McIntire D, Herbelin L, et al. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci 1998 May 13; 841: 769-72 Jaretzki 3rd A, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000 Jul 12; 55 (1): 16-23 Stewart AL, Hays RD, Ware Jr JE. The MOS short-form general health survey: reliability and validity in a patient population. Med Care 1988 Jul; 26 (7): 724-35 Burns TM, Conaway MR, Cutter GR, et al. Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis. Muscle Nerve 2008 Aug; 38 (2): 957-63 Mullins LL, Carpentier MY, Paul RH, et al. Diseasespecific measure of quality of life for myasthenia gravis. Muscle Nerve 2008 Aug; 38 (2): 947-56 Padua L, Evoli A, Aprile I, et al. Health-related quality of life in patients with myasthenia gravis and the relationship between patient-oriented assessment and conventional measurements. Neurol Sci 2001 Oct; 22 (5): 363-9 Paul RH, Nash JM, Cohen RA, et al. Quality of life and well-being of patients with myasthenia gravis. Muscle Nerve 2001 Apr; 24 (4): 512-6 Rostedt A, Padua L, Stalberg EV. Correlation between a patient-derived functional questionnaire and abnormal neuromuscular transmission in myasthenia gravis patients. Clin Neurophysiol 2005 Sep; 116 (9): 2058-64 Rostedt A, Padua L, Stalberg EV. Correlation between regional myasthenic weakness and mental aspects of quality of life. Eur J Neurol 2006 Feb; 13 (2): 191-3 Magni G, Micaglio GF, Lalli R, et al. Psychiatric disturbances associated with myasthenia gravis. Acta Psychiatr Scand 1988 Apr; 77 (4): 443-5 Beekman R, Kuks JB, Oosterhuis HJ. Myasthenia gravis: diagnosis and follow-up of 100 consecutive patients. J Neurol 1997 Feb; 244 (2): 112-8 Lindstrom J. An assay for antibodies to human acetylcholine receptor in serum from patients with myasthenia gravis. Clin Immunol Immunopathol 1977 Jan; 7 (1): 36-43 Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985 Dec; 48 (12): 1246-52 Ohta K, Shigemoto K, Kubo S, et al. MuSK antibodies in AChR Ab-seropositive MG vs AChR Ab-seronegative MG. Neurology 2004 Jun 8; 62 (11): 2132-3 Evoli A, Tonali PA, Padua L, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003 Oct; 126 (Pt 10): 2304-11 Shigemoto K, Kubo S, Jie C, et al. Myasthenia gravis experimentally induced with muscle-specific kinase. Ann N Y Acad Sci 2008; 1132: 93-8 Martignago S, Fanin M, Albertini E, et al. Muscle histopathology in myasthenia gravis with antibodies against MuSK and AChR. Neuropathol Appl Neurobiol 2009 Feb; 35 (1): 103-10

ª 2011 Adis Data Information BV. All rights reserved.

37. Rostedt Punga A, Ahlqvist K, Bartoccioni E, et al. Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes. Clin Neurophysiol 2006 Jul; 117 (7): 1434-43 38. Le Panse R, Cizeron-Clairac G, Cuvelier M, et al. Regulatory and pathogenic mechanisms in human autoimmune myasthenia gravis. Ann N Y Acad Sci 2008; 1132: 135-42 39. Scherer K, Bedlack RS, Simel DL. Does this patient have myasthenia gravis? JAMA 2005 Apr 20; 293 (15): 1906-14 40. Bever Jr CT, Aquino AV, Penn AS, et al. Prognosis of ocular myasthenia. Ann Neurol 1983 Nov; 14 (5): 516-9 41. Chaudhuri A, Behan PO. Myasthenic crisis. QJM 2009 Feb; 102 (2): 97-107 42. Panda S, Goyal V, Behari M, et al. Myasthenic crisis: a retrospective study. Neurol India 2004 Dec; 52 (4): 453-6 43. Berrouschot J, Baumann I, Kalischewski P, et al. Therapy of myasthenic crisis. Crit Care Med 1997 Jul; 25 (7): 1228-35 44. Gajdos P, Chevret S, Clair B, et al. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997 Jun; 41 (6): 789-96 45. Murthy JM, Meena AK, Chowdary GV, et al. Myasthenic crisis: clinical features, complications and mortality. Neurol India 2005 Mar; 53 (1): 37-40; discussion 40 46. Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology 2007 Mar 13; 68 (11): 837-41 47. Luchanok U, Kaminski HJ. Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 2008 Feb; 21 (1): 8-15 48. Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord 2006 Jul; 16 (7): 459-67 49. Vincent A, Leite MI, Farrugia ME, et al. Myasthenia gravis seronegative for acetylcholine receptor antibodies. Ann N Y Acad Sci 2008; 1132: 84-92 50. Bau V, Hanisch F, Hain B, et al. Ocular involvement in MuSK antibody-positive myasthenia gravis [in German]. Klin Monbl Augenheilkd 2006 Jan; 223 (1): 81-3 51. Cikes N, Momoi MY, Williams CL, et al. Striational autoantibodies: quantitative detection by enzyme immunoassay in myasthenia gravis, thymoma, and recipients of D-penicillamine or allogeneic bone marrow. Mayo Clin Proc 1988 May; 63 (5): 474-81 52. Dumitru D. Part IV, Section 25: Neuromuscular junction disorders: electrodiagnostic medicine. 2nd ed. Philadelphia (PA): Hanley & Belfus, 2001 53. AAEM Quality Assurance Committee. Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: summary statement. Muscle Nerve 2001 Sep; 24 (9): 1236-8 54. Howard Jr JF, Sanders DB, Massey JM. The electrodiagnosis of myasthenia gravis and the Lambert-Eaton myasthenic syndrome. Neurol Clin 1994 May; 12 (2): 305-30 55. Zivkovic SA, Shipe C. Use of repetitive nerve stimulation in the evaluation of neuromuscular junction disorders.

Clin Drug Investig 2011; 31 (1)

Autoimmune Myasthenia Gravis

56.

57.

58.

59.

60. 61. 62.

63. 64.

65.

66. 67. 68.

69.

70.

71.

72.

73.

Am J Electroneurodiagnostic Technol 2005 Dec; 45 (4): 248-61 Stickler DE, Sanders DB. Single-fiber EMG, 2009 [online]. Available from URL: http://emedicine.medscape.com/ article/1141438-overview [Accessed 2010 Mar 9] Burns TM, Conaway M, Sanders DB. The MG composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 2010 May 4; 74 (18): 1434-40 Burns TM, Conaway MR, Cutter GR, et al. Construction of an efficient evaluative instrument for myasthenia gravis: the MG composite. Muscle Nerve 2008 Dec; 38 (6): 1553-62 Genkins G, Sivak M, Tartter PI. Treatment strategies in myasthenia gravis. Ann N Y Acad Sci 1993 Jun 21; 681: 603-8 Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet 1934; 1: 1200-1 McEachern D. Prostigmine in myasthenia gravis. Can Med Assoc J 1935; 310-1 Skeie GO, Apostolski S, Evoli A, et al. Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2006 Jul; 13 (7): 691-9 Havard CW, Fonseca V. New treatment approaches to myasthenia gravis. Drugs 1990 Jan; 39 (1): 66-73 Aquilonius SM, Eckernas SA, Hartvig P, et al. Clinical pharmacology of pyridostigmine and neostigmine in patients with myasthenia gravis. J Neurol Neurosurg Psychiatry 1983 Oct; 46 (10): 929-35 Schumm F, Gaertner HJ, Wiatr G, et al. Serum levels of pyridostigmine in myasthenia gravis: methods and clinical significance [in German]. Fortschr Neurol Psychiatr 1985 Jun; 53 (6): 201-11 Osserman KE. Progress report on mestinon bromide (pyridostigmine bromide). Am J Med 1955 Nov; 19 (5): 737-9 Data on file, Meda Group, 2010 eMC. Mestinon (pyridostigmine bromide) 60 mg tablets: summary of product characteristics. 2007 [online]. Available from URL: http://emc.medicines.org.uk/medicine/ 865/SPC/Mestinon+60 mg+Tablets/ [Accessed 2009 May 29] Milner-Brown HS, Mellenthin M, Sharma ML, et al. Quantitative correlation between plasma pyridostigmine levels and neuromuscular function in myasthenia gravis. Neurology 1987 May; 37 (5): 800-3 Young WL, Matteo RS, Ornstein E. Duration of action of neostigmine and pyridostigmine in the elderly. Anesth Analg 1988 Aug; 67 (8): 775-8 eMC. Neostigmine bromide tablets: summary of product characteristics. 2001 [online]. Available from URL: http:// emc.medicines.org.uk/document.aspx?documentId=384 [Accessed 2009 Apr 6] eMC. Neostigmine methylsulphate BP 2.5 mg in 1 mL: summary of product characteristics. 2008 [online]. Available from URL: http://emc.medicines.org.uk/medicine/ 20888/SPC/Neostigmine+Methylsulphate+Injection+BP+ 2.5mg+in+1ml+ (hameln)/ [Accessed 2009 Jun 2] Schwab RS, Marshall CK, Timberlake W. WIN 8077 in treatment of myasthenia gravis; use of N,N’-bis (2-diethylaminoethyl) oxamide bis-2-chlorobenzyl chloride in fifty patients. J Am Med Assoc 1955 Jun 25; 158 (8): 625-8

ª 2011 Adis Data Information BV. All rights reserved.

13

74. sanofi-synthelabo. Mytelase (ambenonium chloride) prescribing information. 2008 July [online]. Available from URL: http://products.sanofi-aventis.us/mytelase/mytelase. html [Accessed 2010 Jun 25] 75. Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 1984 Mar; 15 (3): 291-8 76. Schneider-Gold C, Gajdos P, Toyka KV, et al. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev 2005; (2): CD002828 77. Hart IK, Sharshar T, Sathasivam S. Immunosuppressant drugs for myasthenia gravis. J Neurol Neurosurg Psychiatry 2009 Jan; 80 (1): 5-6; discussion 6 78. Palace J, Newsom-Davis J, Lecky B. A randomized doubleblind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 1998 Jun; 50 (6): 1778-83 79. Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev 2007; (4): CD005224 80. Tindall RS, Rollins JA, Phillips JT, et al. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 1987 Mar 19; 316 (12): 719-24 81. Bonifati DM, Angelini C. Long-term cyclosporine treatment in a group of severe myasthenia gravis patients. J Neurol 1997 Sep; 244 (9): 542-7 82. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000 May; 47 (2-3): 85-118 83. Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability. Neurology 2003 Nov 25; 61 (10): 1438-40 84. Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008 Aug 5; 71 (6): 400-6 85. Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008 Aug 5; 71 (6): 394-9 86. Hehir MK, Burns TM, Alpers JP, et al. Long-term experience with mycophenolate mofetil (MMF) in myasthenia gravis (MG): retrospective analysis of 103 patients [abstract]. Neurology 2009; 72 (11 Suppl. 3): A440 87. Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev 2002; (4): CD002275 88. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 2008; (1): CD002277 89. Chan A, Lee DH, Linker R, et al. Rescue therapy with antiCD20 treatment in neuroimmunologic breakthrough disease. J Neurol 2007 Nov; 254 (11): 1604-6 90. Hain B, Jordan K, Deschauer M, et al. Successful treatment of MuSK antibody-positive myasthenia gravis with rituximab. Muscle Nerve 2006 Apr; 33 (4): 575-80 91. Thakre M, Inshasi J, Marashi M. Rituximab in refractory MuSK antibody myasthenia gravis. J Neurol 2007 Jul; 254 (7): 968-9

Clin Drug Investig 2011; 31 (1)

14

92. Sussman JD, Argov Z, McKee D, et al. Antisense treatment for myasthenia gravis: experience with monarsen. Ann N Y Acad Sci 2008; 1132: 283-90 93. Gronseth GS, Barohn RJ. Thymectomy for myasthenia gravis. Curr Treat Options Neurol 2002 May; 4 (3): 203-9 94. Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000 Jul 12; 55 (1): 7-15 95. Aghajanzadeh M, Khoshrang H, Mohammadzadeh A, et al. Thymectomy for myasthenia gravis: prognostic factors in 70 patients. Asian Cardiovasc Thorac Ann 2007 Oct; 15 (5): 371-5 96. Abt PL, Patel HJ, Marsh A, et al. Analysis of thymectomy for myasthenia gravis in older patients: a 20-year single institution experience. J Am Coll Surg 2001 Apr; 192 (4): 459-64 97. Tsuchida M, Yamato Y, Souma T, et al. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999 Jun; 67 (6): 1563-7

ª 2011 Adis Data Information BV. All rights reserved.

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98. Sanders DB, El-Salem K, Massey JM, et al. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003 Jun 24; 60 (12): 1978-80 99. Magee MJ, Mack MJ. Surgical approaches to the thymus in patients with myasthenia gravis. Thorac Surg Clin 2009 Feb; 19 (1): 83-9, vii 100. Pasnoor M, Wolfe GI, Nations S, et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a US experience. Muscle Nerve 2010 Mar; 41 (3): 370-4 101. ClinicalTrials.gov. Thymectomy trial in non-thymomatous myasthenia gravis patients receiving prednisone therapy. 2009 November 9 [online]. Available from URL: http:// www.clinicaltrials.gov/ct2/show/NCT00294658?term=non-thy momatous&rank=1 [Accessed 2010 Jun 25]

Correspondence: Dr Corrado Angelini, Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128 Padova, Italy. E-mail: [email protected]

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