Diagnosis and management of myasthenia gravis

Transcription

1 Diagnosis and management of myasthenia gravis Sivakumar Sathasivam MRCP (UK), LLM, PhD Myasthenia gravis is the most common primary disorder of neuromuscular transmission and one of the most treatable neurological disorders. In this review, Dr Sathasivam examines the epidemiology, presentation, aetiology, diagnosis and treatment of myasthenia gravis. motor nerve terminal synaptic basal lamina muscle fibre VGSC VGSC VGCC AChE ACh AChR rapsyn AChR F-actin AChR rapsyn MuSK Dok 7 agrin LRP4 LRP4 presynaptic intrasynaptic Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. It is characterised clinically by fluctuating painless muscle weakness, which worsens with exercise and MuSK postsynaptic Figure 1. Normal signalling pathways at the neuromuscular junction of antigen targets involved in myasthenia gravis Acetylcholine (ACh) is synthesised by choline acetyltransferase in motor neurones. An action potential arriving at the motor nerve terminal causes influx of calcium through voltage-gated calcium channels (VGCCs) and triggers the release of ACh from presynaptic vesicles. ACh crosses the synaptic basal lamina and binds to acetylcholine receptors (AChRs). Opening of the AChRs generates an action potential in the postsynaptic muscle fibre via the opening of voltage-gated sodium channels (VGSCs). ACh is hydrolysed by acetylcholinesterase (AChE). During development, the assembly of the postsynaptic apparatus is mediated by agrin, which is released from the motor nerve terminal. Agrin binds to the low-density lipoprotein receptorrelated protein 4 (LRP4) and activates muscle-specific tyrosine kinase (MuSK). Subsequent downstream signalling requires two intracellular adaptors: (a) docking protein 7 (Dok 7), which bridges activation of MuSK to downstream signalling pathways, and (b) rapsyn, which tightly binds to AChRs, attaches them to the contractile protein F-actin and leads to dense AChR clustering at the top of the junctional folds. Three postsynaptic neuromuscular junction antigenic target proteins have been identified in myasthenia gravis: AChR, MuSK and LRP4 towards the end of the day, and improves with rest. It is usually caused by antibodies to postsynaptic proteins, of which three namely nicotinic acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4) have been identified. Advances in pulmonary and ventilatory support in conjunction with treatments developed based on the understanding of the pathophysiology of the disease have made MG one of the most treatable neurological disorders. MG can present to or involve a wide variety of specialists such as internal medicine physicians, GPs, neurologists, ophthalmologists, otorhinolaryngologists, respiratory physicians, cardiothoracic surgeons, oncologists and intensive care specialists. Since the response of MG to treatment is generally favourable, early recognition and prompt treatment is essential in reducing morbidity and mortality from MG. The aim and scope of this review is to provide an up-todate, practical and relevant overview of this eminently treatable condition. Epidemiology The annual incidence of MG is reported to range between 3 and 30 per million population, with the rates at the upper end of the range reported by prospective studies probably providing the most accurate estimates. 1 The incidence rates have increased over time due to greater disease awareness and better diagnostic methods. The prevalence of MG is reported to be approximately 200 per million population now, 2 compared with about 5 per million population between 1915 and This increase can be explained by an aging population, better detection of the antibodies to postsynaptic proteins and longer survival from treatment advances. 4 The influence of geography on incidence and prevalence is difficult to ascertain as most studies have been carried out in Europe and North America. 1,5 In both females and males, the incidence of MG increases with age. Some studies report a bimodal dis- 6 Progress in Neurology and Psychiatry January/February

2 Myasthenia gravis z Review tribution of incidence, especially in females, but this is an inconsistent finding. 1 In young adults, there is a female preponderance, but the converse is true in older people. 6 Type of agent Anti-infective agents Antirheumatics Cardiovascular agents Neuromuscular blockers Topical eye preparations Examples Table 1. Drugs that may exacerbate myasthenia gravis Aminoglycosides, antimalarials, macrolides, polymyxins D-penicillamine, hydroxychloroquine Beta-blockers, calcium-channel blockers Non-depolarising drugs, depolarising drugs Drugs that contain polymyxins, beta-blockers Clinical presentation The extraocular muscles are initially affected in per cent of cases, but virtually all patients will have ocular involvement within two years of disease onset. MG remains purely ocular in 15 per cent of cases. Only 15 per cent of patients progress from ocular MG to generalised MG after two years of disease duration. 7 When MG generalises, the symptoms of muscle weakness typically progress in a craniocaudal direction: from the ocular muscles, to the facial muscles, to the lower bulbar muscles, to the truncal muscles, and finally to the limb muscles. Symptom onset to maximal weakness occurs within the first two years in more than 80 per cent of cases. 3 Despite modern treatments, at least 20 per cent of patients will experience a myasthenic crisis, defined as weakness necessitating intubation and mechanical ventilation, usually within the first two years of diagnosis. Ptosis, due to levator palpebrae weakness, may be unilateral. Extraocular muscle weakness may mimic third, fourth or sixth cranial nerve palsies, or internuclear ophthalmoplegia. Difficulty with eye closure suggests weakness of the orbicularis oculi. Facial muscle weakness may result in an expressionless face, or a snarl when the patient tries to smile. Jaw weakness may interfere with mastication. Nasal speech and nasal regurgitation may occur with palatal weakness, while dysphagia, dysarthria and choking may result from weakness of the pharyngeal and tongue musculature. Dysphonia can occur with laryngeal weakness. In mild disease, neck flexion weakness may be the only finding. Neck extension weakness causes a head drop. Upper extremity weakness is commoner than lower extremity weakness. Mental and physical fatigue are very common features, and can be debilitating. 8 Physical examination should aim to demonstrate pathological fatigability of muscle strength. Manoeuvres that may be used include asking the patient to look up for several minutes (examining for ptosis or extraocular muscle weakness), counting aloud to 100 (listening for a nasal or slurred speech), and repetitively testing the strength of proximal muscles (looking for increasing muscle weakness). If a patient has generalised muscle weakness with no ocular involvement, the diagnosis of MG should be questioned. Muscle weakness in MG can be exacerbated by emotional upset, hot temperature, infection, menstruation, physical exertion, pregnancy, surgery, thyroid disease (hyperthyroidism or hypothyroidism) and many classes of drugs (see Table 1). 9 In most cases, the contraindication to drug use is only relative, in which case the drug is best avoided; but when that is not possible, the patient s symptoms should be closely monitored when the drug is started. Only the macrolide telithromycin is considered absolutely contra indicated in MG. 10 Live vaccines should not be given to immunosuppressed patients. D-penicillamine may induce an immune-mediated MG, which is usually mild, often ocular, and typically remits spontaneously within months of stopping the drug. 11 Aetiopathogenesis Autoantibodies MG is caused by antibodies against proteins in the neuromuscular junction postsynaptic membrane (see Figure 1). Antibodies against AChR are detectable in 50 per cent of MG cases and 85 per cent of generalised MG cases. 12 The anti-achr antibodies are pathogenic because they reduce the number of AChRs at the neuromuscular junction via three mechanisms: anti-achr antibodies bind and crosslink the AChRs, resulting in increased endocytosis and degradation of AChRs by the muscle cell; anti-achrs bind complement factors at the post - synaptic membrane, leading to focal lysis of the postsynaptic folds at the neuromuscular junction by the membrane attack complex; and the destruction of other AChR-associated proteins, such as utrophin, rapsyn and voltage-gated sodium channels, impairs neuromuscular transmission as these proteins are involved in neuromuscular junction formation and maintenance. 13 In up to 70 per cent of patients with no detectable anti-achr antibodies, antibodies against MuSK, a transmembrane protein located at the postsynaptic membrane of the neuromuscular junction, which is functionally interactive with AChR, have been detected. 14 The pathogenic mechanisms of anti- MuSK antibodies are incompletely understood, but appear to involve disrupting the membrane ultra- Progress in Neurology and Psychiatry January/February

3 structure and electrophysiological function of MuSK, and the disassembly of AChR clusters. 15 The prevalence of anti-musk antibody-positive MG is higher in countries nearer the equator. 16 Anti-MuSK antibodies appear to produce a distinct clinical phenotype, with patients more commonly female, a predominance of cranial and bulbar muscle involvement with a higher frequency of respiratory crises, less limb involvement and being uncommonly associated with long-term pure ocular MG. 17,18 Approximately 15 per cent of all patients with generalised MG have no detectable serum anti-achr or anti-musk antibodies. These patients are considered to have seronegative MG. 19 In up to two-thirds of seronegative MG patients, low-affinity anti-achr antibodies have been demonstrated on a special cellbased assay where the AChRs are clustered together with the protein rapsyn. 19 Recently, a new antigen target at the neuromuscular junction, known as low-density lipoprotein receptor-related protein 4 (LRP4), has been identified. LRP4 is an agrin receptor and is required for agrin-induced activation of MuSK, AChR clustering and neuromuscular junction formation. 20 The pathogenic role of anti-lrp4 antibodies appears to involve inhibiting interactions between agrin and LRP4, and reducing AChR clustering. 21 The frequency of anti- LRP4 antibodies in patients with MG appears to vary depending on geographical location, ranging from 2 per cent in Japan 21 to 50 per cent in Germany. 22 A proportion of patients have both anti-lrp4 and anti- MuSK antibodies. 21 It has been reported that the major clinical features of anti-lrp4 antibody-positive MG are not very different from those of anti-achr antibody-positive MG. 22 About 5 per cent of generalised MG patients who continue to have undetectable antibodies probably have pathogenic antibodies against as yet undefined muscle membrane proteins that interact with AChRs. Up to 30 per cent of anti-achr antibody-positive MG patients have additional antibodies that bind to epitopes on skeletal and heart muscle tissue, known as anti-striational antibodies. 23 Anti-striational antibodies to the sarcomeric protein titin, the sarcoplasmic calcium channel ryanodine receptor and the a-subunit of the muscular voltage-gated potassium channel (Kv1.4) have been extensively investigated. Anti-striational antibodies do not have a major pathogenic role, but are markers for thymoma and lateonset disease. They are also associated with autoimmune myocarditis and myositis, and lethal arrhythmias. 24 Although MG patients with anti-kv1.4 antibodies have been associated with severe disease in a Japanese population, a recent study in a Caucasian population demonstrated that the presence of these antibodies was associated with mild MG, suggesting different clinical phenotypes between the two populations. 25 Thymus The thymus is thought to play an important pathogenic role in anti-achr antibody-positive MG, with thymic hyperplasia present in 65 per cent of cases and thymoma present in 10 per cent of cases. 26 Furthermore, MG occurs in 30 per cent of patients with a thymoma as a paraneoplastic phenomenon. 27 A large body of evidence implicates the thymus as the main site of autosensitisation. AChR expression by myoid cells in the thymus, in the presence of the inflammatory environment within the thymus, is thought to lead to the induction and maintenance of the anti-achr auto - immune response in MG. 28,29 In anti-musk antibodypositive patients, there are minimal thymic changes, suggesting no pathogenic role of the thymus in this subtype. In anti-lrp4 antibody-positive MG patients, no thymus disorder has been established thus far. Genetic and environmental factors Certain human leukocyte antigen (HLA) loci and several common variants in HLA-unlinked genes have been associated with MG susceptibility. 30 Many of these risk-associated genes are widely distributed among other autoimmune diseases, suggesting shared pathogenic pathways. Indeed, first-degree relatives of MG patients have a higher incidence of other auto - immune diseases. 31 Several pathogens, such as the Epstein-Barr virus and poliovirus, have been suggested as potential candidates for driving and perpetuating autoimmunity in MG. However, many of the studies give contradictory and inconsistent results. 15 Diagnostic investigations The differential diagnosis of MG is wide (see Table 2). A detailed history and physical examination in conjunction with investigations is often needed to provide diagnostic clues. A systematic review examining the utility of diagnostic tests in MG concluded that only anti-achr antibody testing and single-fibre electro myography (SFEMG) were adequately validated. However, the anti-musk antibody test was not evaluated in this study. 32 Antibody tests All patients with suspected MG should be tested for anti-achr antibodies. The sensitivity of this test is 70-8 Progress in Neurology and Psychiatry January/February

4 Myasthenia gravis z Review Disease Botulism Congenital myasthenic syndromes Cranial nerve palsies Guillain-Barré syndrome Inflammatory myopathies Lambert Eaton myasthenic syndrome Mitochondrial cytopathies Motor neurone disease Oculopharyngeal muscular dystrophy Thyroid eye disease Differentiating clinical features Autonomic and pupillary involvement Onset in infancy or childhood; seronegative; no response to immunotherapy Clinical features occur in distribution of the affected cranial nerves Ascending pattern of muscle weakness; autonomic involvement; areflexia; sensory signs and symptoms No ocular muscle weakness except in orbital myositis; constitutional manifestations common, eg fever, anorexia, weight loss Ocular muscles usually spared; hyporeflexia, autonomic involvement No fluctuation of muscle weakness; often no diplopia in presence of severe ophthalmoplegia Upper motor neurone features; no ocular involvement; muscle wasting Dysphagia typically noticed for solid foods before liquids; tongue weakness and atrophy Proptosis Table 2. Differential diagnoses of myasthenia gravis 95 per cent for generalised MG and per cent for ocular MG. 33 Anti-AChR antibody concentrations do not reliably predict disease severity in individual patients. If anti-achr antibodies are negative, anti- MuSK antibodies should be tested. In seronegative patients, there is a seroconversion rate of 15 per cent after one year. 34 Immunosuppression can occasionally lead to disappearance of antibodies. 34 Detection of anti-striational antibodies may give an indication of the disease phenotype and prognosis. Neurophysiology Repetitive nerve stimulation (RNS) and SFEMG are the most commonly used neurophysiological tests. Results can be misleading in patients on chronic highdose acetylcholinesterase inhibitors. If there is doubt, then it is better, if possible, to stop these drugs for up to a week before the tests. Detailed descriptions of the methodology behind RNS and SFEMG are beyond the scope of this article, but a brief overview of the main principles of these tests, including their sensitivities and specificities are discussed. RNS at stimulation rates of 3-10 Hz typically produces a progressive decrement in the amplitude of the compound muscle action potential. The test is approximately 80 per cent positive in generalised MG, but may be negative in 50 per cent of ocular MG. Overall, sensitivity is approximately 75 per cent. 35 The specificity of RNS is variable and depends partly on which nerve is tested. SFEMG is the most sensitive diagnostic test in MG and should be performed if RNS is normal and a neuro muscular junction disorder is suspected. It shows increased jitter (trial-to-trial variation in the latency from stimulus to response) and intermittent impulse blocking (failure of excitation of muscle fibers) in MG. Sensitivity of SFEMG is as high as 99 per cent in generalised MG and is approximately 80 per cent in ocular MG. 36 The specificity of SFEMG is variable and an abnormal test can be seen in other conditions such as mitochondrial cytopathy, motor neurone disease or radiculopathy. Edrophonium test The edrophonium or tensilon test is a bedside test in which edrophonium chloride, a short-acting acetylcholinesterase inhibitor, is administered. The aim is to demonstrate reversibility of muscle weakness and can only be performed if there is unequivocal weakness present that can be measured objectively. It should be performed double-blind and placebo-controlled. The sensitivity of the test is as high as 88 per cent for generalised MG and 92 per cent for ocular MG, with specificities of 97 per cent for both disease forms. 37 It is prudent to administer atropine prophylactically because of the risk of bradykinesia and cardiac arrest. It is probably best to avoid doing the test in the elderly. Ice pack test A quick method to distinguish ptosis due to MG from other causes is the ice pack test. An ice cube is placed over the drooping eyelid for about two minutes, and if there is improvement in the ptosis, it suggests a neuro muscular transmission disorder. Results pooled from six studies gave this test a sensitivity of 89 per cent and a specificity of 100 per cent. 38 Imaging All MG patients should have computed tomography (CT) or magnetic resonance imaging (MRI) of the Progress in Neurology and Psychiatry January/February

5 thorax to screen for thymoma or thymic hyperplasia. Imaging of the mediastinum should be repeated in the context of a MG relapse after a period of stable disease to exclude the development of a thymoma, which can occur later in the disease course. Treatment In MG, treatment strategies tend to vary even among different physicians practising within the same country. There are no UK guidelines and treatment depends on the experience and familiarity of the treating physician to a particular regimen. Figure 2 depicts a general treatment flowchart that I regularly use, but it is important to note that treatment regimens should be individualised as no single treatment strategy is appropriate for every patient. The present day prognosis of MG is excellent with current treatment regimens having reduced the disease mortality from 70 per cent between 1915 and to less than 5 per cent now. 39 The quality of the scientific evidence for the use of the various treatments in MG is variable (see Table 3). 40 Symptomatic treatment The first-line symptomatic treatment is acetylcholinesterase inhibitors, usually pyridostigmine. 41,42 Other acetylcholinesterase inhibitors are rarely used because of their inferior pharmacodynamic profiles and tolerability. Two observational studies concluded that pyridostigmine was more effective than neostigmine with fewer adverse events. 43,44 Increasing tolerance to pyridostigmine over time may necessitate dose escalation. Anti-MuSK antibodypositive patients tend to show non-responsiveness to pyridostigmine. 45 High doses of pyridostigmine may lead to desensitisation of AChRs, inducing muscle weakness leading to a cholinergic crisis, which can be difficult to distinguish from a myasthenic crisis. If there is any concern, pyridostigmine can be temporarily withdrawn and the patient monitored for improvement. The majority of MG patients will fail to achieve adequate response on pyridostigmine alone and will require further immunosuppression. Short-term immunosuppression Oral prednisolone is the most commonly used firstline short-term immunosuppressant. 46,47 Two double-blind trials of corticosteroids versus placebo gave conflicting results, 48,49 while one open-label randomised trial comparing high-dose corticosteroid versus low-dose corticosteroid showed no significant difference in efficacy. 50 Prednisolone is typically used IVIG or PE in emergency Myasthenia gravis Thymoma Complete response Acetylcholinesterase inhibitor Thymectomy Complete response Incomplete response Add prednisolone + azathioprine (or other immunosuppressants) Incomplete response Young, fit and anti-achr positive Figure 2. A treatment flowchart for the management of myasthenia gravis. IVIG, intravenous immunoglobulin; PE, plasma exchange 10 Progress in Neurology and Psychiatry January/February

6 Myasthenia gravis z Review Treatment Mode of action Evidence Serious adverse Recommendation class * events Symptomatic Pyridostigmine Inhibits acetylcholinesterase Class III Cholinergic crisis First line Short-term immunosuppression Prednisolone Inhibits T-cell activation and Class II Cushingoid features, diabetes, First line impairs function of cells from hypertension, osteoporosis, the monocyte/macrophage psychiatric disorders lineage Long-term immunosuppression Azathioprine Purine antagonist that inhibits Class I Haematopoietic suppression, First line DNA synthesis and cell hepatotoxicity, malignancy, proliferation pancreatitis Ciclosporin Calcineurin-mediated inhibition Class I Hypertension, malignancy, To be considered in patients of T-cell interleukin-2 production nephrotoxicity intolerant of or unresponsive to azathioprine, methotrexate, mycophenolate mofetil or tacrolimus Cyclophosphamide DNA-alkylating agent that Class I Bladder toxicity, haematopoietic To be considered in patients blocks cell proliferation suppression, infertility, malignancy, intolerant of or unresponsive opportunistic infections to azathioprine, methotrexate, mycophenolate mofetil, tacrolimus or ciclosporin Methotrexate Folate antagonist that inhibits de Class II Haematopoietic suppression, Second line in patients intolerant novo synthesis of purines and hepatotoxicity, pneumonitis of or unresponsive to azathioprine pyrimidines Mycophenolate Inhibits T-cell proliferation Class I Haematopoietic suppression, Third line in patients intolerant mofetil by blocking purine synthesis hepatotoxicity, opportunistic of or unresponsive to azathioprine, infections, progressive multifocal methotrexate or tacrolimus leukoencephalopathy Rituximab Chimeric monoclonal Class IV Neutropaenia, opportunistic To be considered only in patients antibody against the B-cell infections, progressive multifocal with severe refractory MG surface marker CD20 leukoencephalopathy unresponsive to other treatments Tacrolimus Calcineurin-mediated Class I Hyperglycaemia, hypertension, Third line in patients intolerant inhibition of T-cell malignancy, nephrotoxicity of or unresponsive to azathioprine, interleukin 2 production methotrexate or mycophenolate mofetil Rapid short-term immunomodulation Immunoglobulin Interference of signalling via Fc Class I Aseptic meningitis, solute-induced First line receptors, neutralisation of renal failure, thrombotic activated complement, suppression complications, volume overload of idiotypic antibodies, modulation of proinflammatory cytokines Plasma exchange Removes circulating antibodies, Class I Air embolism, disturbances in acid- First line cytokines, immune complexes, base homeostasis, hypocalcaemia, and other inflammatory hypotension, infection, pneumothorax, mediators thrombosis, volume overload Long-term immunomodulation Thymectomy Disrupts B-cells producing Class II General risks of surgery Always indicated in patients with a anti-achr antibodies thymoma; in non-thymomatous anti-achr antibody-positive patients, to be considered if MG is not controlled adequately with medical treatment * Evidence Class I - randomised controlled trials available; Class II - controlled trials without randomisation or randomised trials with small patient number; Class III - uncontrolled trials; Class IV - case series Table 3. Treatment options and recommendations in myasthenia gravis Progress in Neurology and Psychiatry January/February

7 as an interim measure while titrating up doses of other immunosuppressants and waiting for those to have maximum effect. A steroid dip due to a temporary worsening of MG four to ten days after starting prednisolone may occur if prednisolone is started at a high dose. To avoid this, it is recommended that prednisolone be started at a low dose on alternate days 51 and gradually titrated upwards. 52 In certain cases, a daily prednisolone regimen may be more suitable, for example in diabetic patients or those intolerant to the fluctuations inherent to an alternate day regimen. Premature or rapid tapering of cortico - steroids should be avoided as this is likely to lead to a relapse of symptoms. Long-term immunosuppression Several different immunosuppressants are used as long-term corticosteroid-sparing agents in MG. 46,53 Azathioprine is the most frequently used. A randomised unblinded trial of azathioprine plus initial prednisolone versus prednisolone alone, 54 and another randomised double-blind trial of azathioprine plus prednisolone versus prednisolone plus placebo 55 have established the efficacy of azathioprine in MG. When azathioprine is not tolerated or if the MG remains difficult to control, alternative immunosuppressants can be used including methotrexate (commonly used second line), mycophenolate mofetil or tacrolimus. A single-blind trial of methotrexate versus azathioprine demonstrated similar efficacy between the two drugs. 56 Two randomised controlled trials failed to show that mycophenolate mofetil plus prednisolone was more effective than prednisolone plus placebo. 57,58 Several reasons have been suggested for these negative results: the generally mild disease status of patients, the better than expected response to prednisolone and the relatively short duration of the trials. 59 A randomised double-blind placebo-controlled trial of tacrolimus plus prednisolone versus prednisolone plus placebo, 60 and another randomised unblinded non-placebo controlled trial of tacrolimus plus corticosteroids with or without plasma exchange versus no tacrolimus plus corticosteroids with or without plasma exchange, 61 have demonstrated that tacrolimus is efficacious in the treatment of MG. Ciclosporin or cyclophosphamide are reserved for severe cases of MG refractory to the other previously mentioned immunosuppressants, but their use is limited by potentially serious adverse events. 40,46 A randomised double-blind trial of ciclosporin monotherapy versus placebo, 62 and another randomised double-blind trial of ciclosporin plus prednisolone versus prednisolone plus placebo 63 have clearly shown that ciclosporin is effective in MG. Cyclophosphamide was shown to be effective in a randomised double-blind trial of intravenous pulsed cyclophosphamide plus prednisolone versus prednisolone plus placebo. 64 Rituximab is a useful option in severe refractory MG unresponsive to other treatments, 65 but this treatment is very expensive. Rapid short-term immunomodulation Intravenous immunoglobulin (IVIG) or plasma exchange (PE) is used in acute severe exacerbations of generalised MG or to optimise muscle strength prior to surgery IVIG and PE are equal first-line treatments because they have similar efficacy. However, because IVIG is easier to administer and associated with fewer adverse events than PE, the former is often preferred. Two randomised controlled trials comparing IVIG with placebo established the efficacy of this treatment in acute severe MG. 69,70 Two randomised controlled trials comparing IVIG to PE showed no significant differences between the two treatments in acute exacerbation of MG 71 or in chronic moderate-to-severe MG. 72 One randomised controlled trial of IVIG versus corticosteroids, 67 and another of PE versus corticosteroids did not reveal significant differences between the treatments tested. 73 Long-term immunomodulation Thymectomy is always indicated in patients with a thymoma because of its malignant potential. 74 However, tumour removal does not always lead to remission of MG. Indeed, MG in thymomatous patients is commonly more severe than in non-thymomatous patients. Thymectomy has been a mainstay of treatment for non-thymomatous MG for over 50 years. However, randomised trials of thymectomy versus medical treatment are lacking. A rigorous evidence-based analysis of 28 studies published between 1953 and 1998 concluded that it only might improve the chance of remission as the benefit of surgery was generally small. 75 Thymectomy within the first three years of diagnosis may lead to a better response. The procedure is commonly restricted to patients under the age of years because older patients usually have an atrophic thymus. Anti-MuSK antibody-positive patients tend to have a poorer response, probably explained by the lack of typical thymus pathology in these patients. There is controversy as to whether a minority of seronegative MG patients benefit from thymectomy. An ongoing international thymectomy 12 Progress in Neurology and Psychiatry January/February

8 Myasthenia gravis z Review trial in non-thymomatous patients may help clarify further the right candidates for thymectomy. Conclusion Advances in our understanding of the pathophysiology of MG have led to more effective treatments for this condition. Earlier disease recognition combined with prompt appropriate treatment are key factors in improving the prognosis of MG. Therefore, the need to educate and improve disease awareness is important in the diagnosis and management of this eminently treatable neurological disorder. Declaration of interests None declared. Dr Sathasivam is a Consultant Neurologist at The Walton Centre NHS Foundation Trust, Liverpool References 1. McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic literature review. Neuroepidemiology 2010;34: Phillips LH 2nd. The epidemiology of myasthenia gravis. Ann NY Acad Sci 2003;998: Grob D, Brunner N, Namba T, et al. Lifetime course of myasthenia gravis. Muscle Nerve 2008;37: Phillips LH 2nd, Torner JC. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology 1996;47: Carr AS, Cardwell CR, McCarron PO, et al. A systematic review of population-based epidemiological studies in myasthenia gravis. BMC Neurol 2010;10: Alshekhlee A, Miles JD, Katirji B, et al. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology 2009;72: Bever CT Jr, Aquino AV, Penn AS, et al. Prognosis of ocular myasthenia. Ann Neurol 1983;14: Paul RH, Cohen RA, Goldstein JM, et al. Fatigue and its impact on patients with myasthenia gravis. Muscle Nerve 2000;23: Pascuzzi RM. Medications and myasthenia gravis (a reference for health care professionals). Myasthenia Gravis Foundation of America, Accessed March 5, Farrugia ME. Myasthenic syndromes. J R Coll Physicians Edinb 2011;41: Penn AS, Low BW, Jaffe IA, Luo L, et al. Drug-induced autoimmune myasthenia gravis. Ann NY Acad Sci 1998;841: Lindstrom JM, Seybold ME, Lennon VA, et al. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976;26: Vrolix K, Fraussen J, Molenaar PC, et al. The auto-antigen repertoire in myasthenia gravis. Autoimmunity 2010;43: 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;7: Cavalcante P, Bernasconi P, Mantegazza R. Autoimmune mechanisms in myasthenia gravis. Curr Opin Neurol 2012;25: Vincent A, Leite MI, Farrugia ME, et al. Myasthenia gravis seronegative for acetylcholine receptor antibodies. Ann NY Acad Sci 2008;1132: Lavrnic D, Losen M, Vujic A, et al. The features of myasthenia gravis with autoantibodies to MuSK. J Neurol Neurosurg Psychiatry 2005;76: Evoli A, Tonali PA, Padua L, et al. Clinical correlates with anti-musk antibodies in generalized seronegative myasthenia gravis. Brain 2003;126: Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to acetylcholine receptors in seronegative myasthenia gravis. Brain 2008;131: Zhang B, Luo S, Wang Q, et al. LRP4 serves as a coreceptor of agrin. Neuron 2008;60: Higuchi O, Hamura J, Motomura M, et al. Autoantibodies to lowdensity lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011;69: Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChRand MuSK-antibody-negative myasthenia gravis. J Neurol 2012;259: Gilhus NE. Autoimmune myasthenia gravis. Expert Rev Neurother 2009;9: Suzuki S, Utsugisawa K, Nagane Y, et al. Three types of striational antibodies in myasthenia gravis. Autoimmune Dis 2011;2011: Romi F, Suzuki S, Suzuki N, et al. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. J Neurol 2012;259: Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis 2007;2: Marx A, Willcox N, Leite MI, et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 2010;43: Le Panse R, Cizeron-Clairac G, Cuvelier M, et al. Regulatory and pathogenic mechanisms in human autoimmune myasthenia gravis. Ann NY Acad Sci 2008;1132: Cavalcante P, Le Panse R, Berrih-Aknin S, et al. The thymus in myasthenia gravis: site of innate autoimmunity? Muscle Nerve 2011;44: Giraud M, Vandiedonck C, Garchon HJ. Genetic factors in autoimmune myasthenia gravis. Ann NY Acad Sci 2008;1132: Pourmand R. Myasthenia gravis. Dis Mon 1997;43: Benatar M. A systematic review of diagnostic tests in myasthenia gravis. Neuromuscul Disord 2006;16: Howard JF Jr. Myasthenia gravis. A manual for the health care provider. Myasthenia Gravis Foundation of America LinkClick.aspx?fileticket=S472fPAE1ow%3d&tabid=125. Accessed 5 March, Chan KH, Lachance DH, Harper CM, et al. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 2007;36: Oh SJ, Kim DE, Kuruoglu R, et al. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve 1992;15: AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medicine. Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert- Eaton myasthenic syndrome. Muscle Nerve 2001;24: Nicholson GA, McLeod JC, Griffiths LR. Comparison of diagnostic tests in myasthenia gravis. Clin Exp Neurol 1983;19: Larner AJ. The place of the ice pack test in the diagnosis of myasthenia gravis. Int J Clin Pract 2004;58: Grob D, Arsura EL, Brunner NG, et al. The course of myasthenia gravis and therapies affecting outcome. Ann NY Acad Sci 1987;505: Sathasivam S. Current and emerging treatments for the management of myasthenia gravis. Ther Clin Risk Manag 2011;7: Maggi L, Mantegazza R. Treatment of myasthenia gravis. Focus on pyridostigmine. Clin Drug Investig 2011;31: Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev 2011;2:CD Schwarz H. Mestinon (pyridostigmine bromide) in myasthenia gravis. Can Med Assoc J 1956;75: Simpson JF, Westerberg MR, Magee KR. Myasthenia gravis. An analysis of 295 cases. Acta Neurol Scand 1966;42 Suppl 23: Hatanaka YH. Nonresponsiveness to anticholinesterase agents in patients with MuSK-antibody-positive MG. Neurology 2005;65: Sathasivam S. Steroids and immunosuppressant drugs in myasthenia gravis. Nat Clin Pract Neurol 2008;4: Schneider-Gold C, Gajdos P, Toyka KV, et al Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev 2005;2:CD Howard FM Jr, Duane DD, Lambert EH, et al. Alternate-day prednisone: preliminary report of a double-blind controlled study. Ann NY Acad Sci 1976;274: Lindberg C, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand Progress in Neurology and Psychiatry January/February

9 1998;97: Zhang J, Wu H. Effectiveness of steroid treatment in juvenile myasthenia gravis. Chinese J Pediatrics 1998;36: Warmolts JR, Engel WK. Benefit from alternate-day prednisone in myasthenia gravis. N Engl J Med 1972;286: Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010;17: Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev 2007;4:CD Myasthenia Gravis Clinical Study Group. A randomised clinical trial comparing prednisolone and azathioprine in myasthenia gravis. Results of a second interim analysis. J Neurol Neurosurg Psychiatry 1993;56: Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 1998;50: Heckmann JM, Rawoot A, Bateman K, et al. A single-blind trial of methotrexate versus azathioprine as steroid-sparing agents in myasthenia gravis. BMC Neurol 2011;11: Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008;71: Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008;71: Silvestri NJ, Wolfe GI. Myasthenia gravis. Semin Neurol 2012;32: Yoshikawa H, Kiuchi T, Saida T, et al. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011;82: Nagane Y, Utsugisawa K, Obara D, et al. Efficacy of low-dose FK506 in the treatment of myasthenia gravis a randomized pilot study. Eur Neurol 2005;53: Tindall RSA, Rollins JA, Phillips JT, et al. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. New Engl J Med 1987;316: Tindall RS, Phillips JT, Rollins JA, et al. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann NY Acad Sci 1993;681: De Feo LG, Schottlender J, Martelli NA, et al. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle Nerve 2002;26: Maddison P, McConville J, Farrugia ME, et al. The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2011;82: Sathasivam S. Evidence for use of intravenous immunoglobulin and plasma exchange in generalised myasthenia gravis. Adv Clin Neurosci Rehabil 2009;9: Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 2008;1:CD Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev 2004;4:CD Wolfe GI, Barohn RJ, Foster BM, et al. Myasthenia Gravis-IVIG Study Group. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002;26: Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis. A randomized controlled trial. Neurology 2007;68: Gajdos P, Chevret S, Clair B, et al. Clinical trial of plasma exchange and high dose immunoglobulin in myasthenia gravis. Ann Neurol 1997;41: Ronager J, Ravnborg M, Hermansen I, et al. Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artif Organs 2001;25: Gajdos P, Simon N, de Rohan-Chabot P, et al. Long-term effects of plasma exchange in myasthenia. Results of a randomized study. Presse Med 1983;12: Zielinski M. Management of myasthenic patients with thymoma. Thorac Surg Clin 2011;21: 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;55: Progress in Neurology and Psychiatry Jan/Feb 2014