Clinical & Experimental. Neuroimmunology. Japanese clinical guidelines for myasthenia gravis: Putting into practice

REVIEW ARTICLE Japanese clinical guidelines for myasthenia gravis: Putting into practice Hiroyuki Murai Clinical & Experimental Neuroimmunology Clinical and Experimental Neuroimmunology 6 (2015) 21 31 Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Keywords guidelines; immunosuppressants; myasthenia gravis; steroids; thymectomy Correspondence Hiroyuki Murai, MD, PhD, Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel: +81-92-642-5340 Fax: +81-92-642-5352 Email: hmurai@neuro.med.kyushu-u.ac.jp Received: 1 December 2014; revised: 3 December 2014; accepted: 3 December 2014. Abstract Treatment of myasthenia gravis has depended largely on high-dose corticosteroids for decades. Although this procedure remarkably reduced the mortality rate of myasthenia gravis, it highlighted issues such as the adverse-effects of steroids and reduction in quality of life. With the recent discovery of novel autoantibodies, a numbers of alternative therapeutic options have become available. The new Japanese clinical guidelines for myasthenia gravis were published in 2014, and they proposed a novel treatment strategy utilizing these therapeutic options, which might replace highdose steroids. They also proposed a draft of new diagnostic criteria. The present review introduces the essence of these guidelines and shares the fundamental philosophy of the treatments that value the patients quality of life. Introduction Myasthenia gravis (MG) is a most common autoimmune disease affecting the neuromuscular system. The prevalence of MG is rising not only in Japan, but also worldwide. 1,2 It is noteworthy that lateonset MG is increasing in particular. 1,3 6 In the 1960s, an antibody against the acetylcholine receptor (AChR) was found to be pathogenic in MG. 7 Recently, muscle-specific receptor tyrosine kinase (MuSK) antibody and the autoantibody to low-density lipoprotein receptor-related protein 4 (Lrp4) were reported, and have been considered as pathological autoantibodies of MG. 8,9 Thanks to high-dose oral corticosteroids, the mortality of MG has reduced remarkably. 10 However, this approach often necessitates the long-term treatment with high-doses of steroids, and steroid-related adverse reactions became common impairing the quality of life (QOL) for patients with MG. 11,12 Because a number of new treatment options are now available, it is time to reconsider high-dose steroid treatment for MG and seek a novel strategy based on patients QOL. Furthermore, it has recently been considered that thymectomy for non-thymomatous MG patients is no longer the first-line treatment. Because the Japanese treatment guidelines for MG published in 1993 had become obsolete, the Japanese Society of Neurology, Japanese Society for Neuroimmunology, Japanese Society of Neurological Therapeutics, The Japanese Society of Child Neurology, and the Neuroimmunological Disease Research Committee of Japan s Ministry of Health, Labour and Welfare called a Committee of Clinical Guidelines for MG. Thus, the new Japanese clinical guidelines for MG were published in 2014. 13 The present review introduces the essence of the new Japanese clinical guidelines for MG. 13 We believe that the new guidelines offer a breakthrough in the treatment of MG. Diagnostic criteria A long time has passed since the current MG diagnostic criteria were developed, during which the understanding of the pathology of MG has improved and parts of the diagnostic criteria have become obsolete. Thus, the diagnostic criteria have been reviewed and draft revisions to the criteria have been prepared (Table 1). The new draft criteria include descriptions of MuSK antibodies and information about MG diagnosis based on an eyelid 2015 Japanese Society for Neuroimmunology 21

Japanese guidelines for MG H. Murai Table 1 Proposed diagnostic criteria for myasthenia gravis A Symptoms 1. Blepharoptosis 2. Eye movement disorder 3. Facial muscle weakness 4. Dysarthria 5. Dysphagia 6. Mastication disorder 7. Cervical muscle weakness 8. Limb muscle weakness 9. Respiratory disorder Note: These symptoms show easy fatigability and daily uctuations B Pathogenic autoantibodies 1. Anti-acetylcholine receptor antibody-positive 2. Anti-muscle-specic receptor tyrosine kinase antibody-positive C Neuromuscular junction disorders 1. Positive on eyelid easy fatigability test 2. Positive on ice pack test 3. Positive on edrophonium chloride (Tensilon) test 4. Positive on repetitive stimulation test 5. Jitter increase on single ber electromyography test D Determination Diagnosis of myasthenia gravis made if either of the below is true: 1. One or more items from A is true and any item of B is true 2. One or more items from A is true, and any item of C is true and other diseases can be ruled out fatigability test or ice pack test. 14 17 In the current diagnostic criteria, information on AChR antibodies and information on tests, such as the repetitive stimulation test, are treated equally in the section on laboratory findings. In the new draft of these criteria, they are described in separate sections. The diagnosis of MG is easy if the pathogenic autoantibody test is positive, but in the current circumstances of low single-fiber electromyography availability, it is often difficult if both AChR antibody and MuSK antibody tests are negative. In fact, it is not unusual to see patients who are not diagnosed with MG and thereby not receiving proper treatment. Therefore, implementation of plasma exchange (PE)/plasmapheresis (PP) as a therapeutic diagnosis might be considered when other diseases are well differentiated and clinical symptoms strongly suggest MG, even if the presence of pathogenic autoantibodies or neuromuscular junction disorder cannot be shown. Fundamental philosophies of treatment Full remission is difficult in cases of adult-onset MG, so treatment strategies should take into account the fact that treatment might be prolonged, and aim for maintaining health-related QOL and mental health The first goal in MG treatment is minimal manifestations (MM) with oral prednisolone (PSL) of 5 mg/day or below, and treatment strategies should strive to attain this level as rapidly as possible In cases of generalized MG, immunotherapy should be carried out from early stages in order to shorten the period of time during which MG symptoms interfere with daily activities. Dosages of drugs ingested over the long term should be minimized Immunotherapy is always the primary method of treating generalized MG, with anticholinesterase agents serving a supplementary role In the 1970s and 1980s, the main treatment method became high doses (1 mg/kg or 50 60 mg/ day) of oral corticosteroids resulting in decreased prevalence of severe cases and fatalities, as well as improved life expectancy. 10,12 Although this method of treatment did improve MG symptoms, the approach often led to long-term ingestion of midlevel or higher doses of steroids, and steroid-related adverse reactions were common. 11,12,18 Complete remission rates for MG remained low (15% or below), even after oral steroid treatments became widespread, and many patients were forced to use oral steroids for long periods of time. 10 Recently, it has been pointed out that many patients suffer impaired QOL as a result of persistent symptoms or insufficiently reduced oral steroid levels. 11,18 20 Physicians also often fail to realize the extent of patient dissatisfaction with their symptoms and disease state. 21 In most cases, the course of MG is long-term (essentially life-long). 22 Because full remission is difficult to achieve, the treatment goal should be realistically achievable for most patients and enable high QOL-related patient satisfaction; efforts should then focus on achieving these goals as rapidly as possible. There is a consensus beyond the level of evidence among most specialists that treatment must focus more on patient QOL. 11,18,19,21,23 According to cross-sectional multicenter studies, factors significantly related to poor QOL or mental health are insufficient improvement in movement 22 2015 Japanese Society for Neuroimmunology

H. Murai Japanese guidelines for MG symptoms and levels of oral steroids. 24 Long-term steroid use can impair QOL in a variety of ways, from worsening physical appearance to causing diabetes mellitus and osteoporosis, as well as contributing significantly to depression. 11,19,24 PSL clearly increases the prevalence of depression and moonshaped face from a daily dosage level of 7.5 10 mg/ day, inhibiting patient social activity and lowering QOL. 25 Therefore, long-term oral steroid use should be maintained at lower doses. Analysis of data from both cross-sectional and longitudinal multicenter studies shows that MM with PSL 5 mg/day or lower, a treatment goal achievable by more patients than complete stable remission (CSR), results in patient satisfaction essentially equivalent to CSR. 11 This guideline does not negate traditional treatment methods of high-dose steroids with escalation and deescalation. However, such treatment methods do invite deteriorated QOL as a result of steroids; therefore, they should be used with caution and include efforts to reduce steroid dosage. Success rates are low for achieving MM with PSL 5 mg/day or lower using dose escalation and de-escalation. 18 One suggested strategy for increasing success rates is reducing oral steroid dosage and using calcineurin blockers early, then using rapidly-acting, aggressive treatments to improve remaining symptoms quickly (early aggressive treatment strategy). 18 One example of such a powerful treatment is combined PE/PP and steroid pulse. 18 If doctors have little experience with this type of therapy, or if patients are elderly, high doses of intravenous immunoglobulin (IVIg) are a safe and effective alternative form of aggressive treatment. 26 Although evidence is scant, anticholinesterase drugs clearly improve MG symptoms, and are currently considered first-line treatments. However, for generalized MG, immunotherapy remains the central treatment approach, with anticholinesterase serving as supportive treatment. Dosage levels should be kept to a minimum, and treatment not be continued indefinitely, but discontinued once immunotherapy sufficiently reduces symptoms. Thymectomy for non-thymomatous patients Thymectomies might be effective and could be considered for non-thymomatous early onset MG patients (EOMG) in cases of anti-achr antibody positive and thymic hyperplasia in the early stages of the disease Thymectomy is not considered first-line treatment for non-thymomatous late-onset MG (LOMG), and the procedure should be considered carefully in these cases Thymectomy should be carried out without doubt for thymoma-associated MG (TAMG) patients. There are no reports providing accurate analysis of thymectomy for non-thymomatous MG, so the efficacy of this treatment remains unclear. 27 Patients who received thymectomy showed superior remission rates (33% vs 10%) compared with patients who did not in a study on non-thymomatous MG patients below the age of 45 years; but in a different study on non-thymomatous MG patients aged 40 years or older, there was no difference in low remission rates between patients who did or did not receive thymectomies (7.7% vs 7.7%). 27 There are reports of higher complete remission rates and efficacy in young-onset MG patients, results that agree with thymectomy efficacy expected given the status of the thymus. 28,29 According to Grob et al., 30 patients receiving a thymectomy in 1940 1957 showed a remission rate superior to those who did not, but there was no difference between the two groups in 1958 1965 and 1965 1985. This could result from the inability to detect the efficacy of thymectomies because of the spread of immunotherapy, or a reduced incidence in the form of the disease for which thymectomy is effective. Thymectomy should be considered for patients for whom the surgery s efficacy can be expected to exceed immunotherapy methods. Thymic involvement is common in some aspects of MG, but mechanisms and the degree of involvement differ according to thymus histology, age of onset and time since onset. 31 Thymic abnormalities might consist of thymic hyperplasia, which is present in approximately half of cases of EOMG (approximately 30% of all MG cases), or thymoma (approximately 20% of all MG cases). 31 Various sources show that thymectomy is effective in cases of non-thymomatous MG only for some EOMG patients; these cases are young age of onset (age of up to about the 30s), with anti-achr antibody and thymic hyperplasia in the early stages of the disease. 32 However, before surgery, it is difficult to radiologically diagnose thymic hyperplasia with a high degree of accuracy, and there are no predictive molecular markers for thymectomy efficacy. As long as efficacy of thymectomy in cases of non-thymomatous MG remains unsettled, operations should only be carried out after obtaining fully informed consent. 2015 Japanese Society for Neuroimmunology 23

Japanese guidelines for MG H. Murai Currently, patients with LOMG, which accounts for approximately half of all MG cases, show thymic atrophy no different from healthy individuals. 31,32 Long-term complete remission is difficult to attain in cases of LOMG regardless of thymectomy, but reactions to immunotherapy are good, and it is often easy to achieve the goal of MM with PSL 5 mg/day or below. Currently, thymectomy is not considered first-line treatment for non-thymomatous LOMG. In clinical practice, one problematic issue is the age at which to divide EOMG (thymectomy might be considered) and LOMG (thymectomy fundamentally not carried out). Thymic hyperplasia becomes less prevalent in cases of onset after approximately 40 years-of-age, and is rare in non-thymomatous cases of onset at 50 years-of-age or later. 31,32 However, there have been reports of thymectomies proving effective in cases of onset at 50 years-of-age or later. 33 The relationship between disease characteristics and age of onset differs according to patient, so a single age cannot be set to distinguish between EOMG and LOMG; however, the division is thought to occur somewhere between 40 and 60 years-ofage. In clinical research, the age of division is most often set at 50 years, based on ages at which the male-to-female ratios change and age-of-onset histogram findings. 34 Recently, the boundary between EOMG and LOMG was reported to be approximately 45 years-of-age from a statistical perspective using two-step cluster analysis. 35 Oral immunosuppressive therapy High-dose oral steroids utilizing dose escalation and de-escalation are effective against MG, but long-term use of oral steroids above a certain dosage level is known to involve a number of problems. Therefore, this approach is now being reconsidered, and high-dose oral steroids require careful consideration given the other treatment options available Long-term oral steroids cause a high incidence of adverse reactions, as well as worsened QOL and mental health; therefore, high doses should be avoided Calcineurin inhibitors (cyclosporine and tacrolimus) are more effective in patients with a shorter disease duration Rates of complete remission remain low for MG, forcing many patients to maintain oral immunotherapy regimens for long periods. 10,22,36,37 Long-term steroid use above a certain level makes adverse reactions likely, causing deteriorated QOL and mental health. 22,37,38 As long as complete remission remains difficult to achieve, treatment plans for oral immunotherapy should attempt to maintain QOL. Further, because of the increase in LOMG and accumulation of long-term patients, there are now more elderly MG patients requiring care compared with 20 years ago. 6 Current first-line choices of oral immunotherapy for MG are still corticosteroids. 22,38 There is no room for doubt that corticosteroids are effective in improving MG symptoms, but there have been no randomized controlled trials studying oral steroids in MG patients. 38 There are also no data supporting the claim that treatment with high-dose oral steroids increases rates of complete remission in MG, and epidemiological research shows no change in complete remission rates before and after use of oral steroids became widespread. 10 Problems with oral steroids become pronounced at a daily dosage of 7.5 10 mg PSL. 25 Long-term oral steroid dosage should be maintained at 10 mg/day or lower, and preferably 5 mg/day or lower. 24 A recent report argued that achievement of MM or better at peak PSL dose and combined use of PE/PP and/or IVIg were associated positively, and total PSL dose during the past year was associated negatively with present MM or better status. 39 In other words, higher PSL dose and longer PSL treatment do not ensure better outcome. Therefore, in the absence of a good response, the PSL dose should be decreased by combining with modalities such as PE/PP or IVIg. The calcineurin inhibitors, cyclosporine and tacrolimus, have both been shown to the efficacious against MG. 40,41 When calcineurin inhibitors were first introduced in Japan, regulations stipulated they be used only when steroid therapy proved insufficient. However, analysis of clinical results showed that calcineurin inhibitors were most effective in patients with short duration of illness, and they are now considered useful for aggressively treating the early stages of the disease. 42 Azathioprine has also been shown to be effective against MG, but it is not covered by the national insurance system and is not commonly used in Japan. Cyclosporine is both fast-acting and highly effective at suppressing symptoms at a dosage of 5 mg/ kg/day (high-dosage level for MG treatment). 43 However, it is not unusual for blood concentration trough levels to exceed 200 ng/ml (especially in obese patients), and neither mildly elevated creatinine nor hypertension are rare. 43 Adverse reactions 24 2015 Japanese Society for Neuroimmunology

H. Murai Japanese guidelines for MG are also not uncommon, including dizziness, swollen or inflamed gums and hair growth. 40,43 Although elevated creatinine and hypertension will improve once the dose is reduced, high doses should only be given under strict monitoring. 43 In general, a starting dose of 3 mg/kg/day is recommended from the perspective of safety. One significant benefit of cyclosporine is that impaired glucose tolerance is rarely a problem, often making the treatment a good choice for elderly MG patients. Tacrolimus is about as effective in treating MG symptoms as cyclosporine. 42 Regulations stipulate a low dose of 3 mg/day for MG treatment, a level at which there is hardly ever creatinine elevation. Blood concentration also does not usually require checking as frequently as with cyclosporine. Tacrolimus is considered easy to administer, with few adverse events. However, especially for elderly MG patients, the problem lies with its effect of worsening glucose tolerance. If tacrolimus is used in patients with existing impaired glucose tolerance or diabetes mellitus, this impaired glucose tolerance will almost always become exacerbated. Thus, regular testing is necessary, as well as either initiation of diabetes mellitus treatment or strengthening of existing treatments as required. It is difficult to state what treatment methods should be attempted for rapid improvement when oral PSL (10 mg/day or below) and calcineurin inhibitors (cyclosporine or tacrolimus) fail to control symptoms sufficiently. Increased dosages of oral steroids might be unavoidable if powerful treatments (such as PE/PP, steroid pulse or IVIg) are unfeasible. However, in these cases, all efforts should be made to reduce dosage rapidly. High-dose intravenous methylprednisolone treatment High-dose intravenous (IV) methylprednisolone is effective against generalized MG (grade B), but entails transient initial exacerbation. Therefore, such treatment requires caution and measures to protect the patient Intermittent treatment with high-dose IV methylprednisolone improves MG symptoms while reducing quantities of oral steroids and steroid-related adverse reactions Initial exacerbation of symptoms caused by highdose IV methylprednisolone might be partially mitigated by carrying out the treatment directly after PE/PP High-dose IV methylprednisolone is both fast-acting and effective, with extremely mild long-term adverse reactions. 38,44,45 It does have the drawback of initial exacerbation during MG treatment, but this is often short-lasting (2 5 days from the day after treatment). 44,45 Insomnia and dizziness can also occur. If initial exacerbation can be overcome or tolerated, high-dose IV methylprednisolone is a convenient, effective treatment option. Of all corticosteroids treatment for MG, only highdose IV methylprednisolone has been shown to be effective compared with a placebo in a randomized controlled trial. 38,44 Initial exacerbation of symptoms caused by high-dose IV methylprednisolone might be partially mitigated by carrying out the treatment directly after PE/PP. 18,46 It should only be carried out by a doctor with abundant experience with the treatment, or under the supervision of such a doctor. The treatment is fundamentally carried out on an inpatient basis. High-dose IV methylprednisolone is not appropriate as a first treatment for generalized MG. There is a risk of crisis as a result of initial exacerbation, especially in patients of MG Foundation of America (MGFA) Class III or above, or in patients with bulbar symptoms. This treatment should preferably be carried out after oral prednisolone of 5 10 mg/day with or without calcineurin inhibitors. Various measures can be taken to reduce risk, such as: (i) reducing the dosage from normal 1000 mg to 500 mg; (ii) not administering for 3 days consecutively, but instead administering once and then observing for 2 5 days; or (iii) using directly after PE/PP. If using steroid pulse therapy, prepare for crises and ensure the patient has been fully informed. IVIg treatment IVIg is effective for moderate to serious cases of MG. Efficacy in mild cases or ocular MG is unclear (grade B). IVIg improves exacerbated MG symptoms at approximately the same level of efficacy as PE/PP. There is no evidence regarding long-term effects (grade B). The standard therapy regimen is 0.4 g/kg/day for 5 continuous days. The speed of infusion should comply with package insert instructions (grade B). IVIg increases blood viscosity, so dosage quantities and infusion speed should be adjusted appropri- 2015 Japanese Society for Neuroimmunology 25

Japanese guidelines for MG H. Murai ately based on the patient s overall condition if the patient has concomitant cardiovascular or cerebrovascular conditions (grade B). IVIg is more useful than PE/PP for elderly patients or patients with unstable circulatory dynamics IVIg is widely used for autoimmune neuromuscular diseases. Many details of the mechanism of action of IVIg against MG remain unknown, but it is hypothesized due to the inhibition of complement cascade and competition with autoantibodies in the neuromuscular junction s postsynaptic membrane. 47 Compared with PE/PP, IVIg therapy requires less special expertise and experience on the part of the practitioner; it also offers greater safety, because it does not entail transient post-therapy exacerbation. Two randomized controlled trials have reported that IVIg and PE/PP have equivalent efficacy. 48,49 However, these studies do not evaluate the longterm effects. Based on a large-scale cohort study including 1606 hospitalized patients from a USA database, Mandawat et al. 50 recommended IVIg therapy for exacerbated symptoms in patients who are elderly or have serious respiratory or circulatory concomitant illnesses. IVIg affects systemic circulatory dynamics by increasing blood viscosity, so dosage quantities and administration rates must be adjusted for each individual based on risk factors, such as cerebrovascular disorders, cardiac failure, renal failure and other conditions. 51 PE/PP Simple PE, double filtration plasmapheresis (DFPP) and immunoadsorption plasmapheresis (IAPP) all have equivalent effects PE/PP is also effective against anti-achr antibodynegative MG (seronegative MG; grade C1). PE and DFPP are recommended for anti-musk antibody-positive MG (MuSK-MG; grade C1). PE/PP is carried out in cases of MG in order to temporarily improve clinical symptoms by removing causative substances, such as anti-achr antibodies and anti-musk antibodies, from circulating plasma. PE/PP is indicated for MG when symptoms become worse, during acute exacerbation (especially in crises), before thymectomy or when other treatments are insufficiently effective. One proposed approach to treating generalized MG is an early powerful treatment of combined PE/PP and steroid pulse therapy to rapidly improve symptoms. 18 Studies comparing the efficacy of different types of PE/PP report equivalent effects among PE, DFPP and IAPP. 52,53 Specific aspects, such as the number of procedures and volumes of plasma processed, have yet to be sufficiently studied. PE/PP is also effective against anti-achr antibody-negative MG. 52,54 According to a case report, IVIg and IAPP were both ineffective in treating MuSK-MG, whereas PE was remarkably effective. 55 IAPP was likely ineffective because immunoglobulin G4 is the primary component of anti-musk activity, and Immusorba TR350 has little immunoadsorption effect. One study states that DFPP clears anti-musk antibodies, leading to improved clinical symptoms, so PE or DFPP are recommended for MuSK-MG. 56 Treatment for anti-achr antibody-negative patients (including MuSK-MG) There is no evidence that thymectomy is effective in MuSK-MG (grade C2). Anticholinesterase is remarkably effective in fewer MuSK-MG patients than anti-achr antibody-positive patients (AChR-MG), with some MuSK-MG patients showing outcomes of no change or symptom exacerbation. Therefore, the drug should be used from small quantities and only with caution MuSK-MG patients show dysphagia and crises at higher rates than AChR-MG patients; a combination of steroids and immunosuppressive agents is used from onset, with aggressive treatment with PE or IVIg when symptoms become worse Patients testing negative for both anti-achr antibodies and anti-musk antibodies (double seronegative MG [DS-MG]) should receive thymectomy in case of thymoma, and are recommended to receive PE/PP in non-thymoma cases for purposes of both treatment and diagnosis Approximately 15% of MG patients overall are negative for serum anti-achr antibodies, and some of these are positive for anti-musk antibodies. Patients who test negative for both anti-achr and anti-musk antibodies are referred to as double seronegative MG (DS-MG). However, the disease 26 2015 Japanese Society for Neuroimmunology

H. Murai Japanese guidelines for MG expression is not uniform in all DS-MG patients; at least some are thought to possess anti-achr antibodies (clustered AChR 57 ) or anti-musk antibodies below the limit of detection. There are reports of new pathogenic autoantibodies, such as anti-lrp4 antibodies in DS-MG patients, but at present no specific clinical presentation DS-MG patients has emerged. 9 DS-MG status might also sometimes make diagnosis of MG itself more difficult. MuSK-MG patients very rarely have concomitant thymoma, and most studies are skeptical of the efficacy of thymectomy. Pathological examination of thymuses resected from MuSK-MG patients have been largely normal. 58,59 Thymectomy is not generally recommended in these cases. 58 60 MuSK-MGpatientsshowpoorreactionstoanticholinesterase agents compared with AChR-MG patients. 61,62 This is related to the fact that approximately 50% of MuSK-MG patients tested positive in an edrophonium chloride test, a much lower rate than AChR-MG patients. A relatively large number of patients also exhibited cholinergic adverse reactions during the test, including exacerbated symptoms, increased saliva secretion, and GI symptoms. These factors suggest that anticholinesterase agents should be used in MuSK-MG patients from small doses and with sufficient precautions. 61 Currently, most MuSK-MG patients begin treatment with steroids, followed by the addition of immunosuppressive agents as necessary. Symptom exacerbation is treated with combinations of treatments, such as steroid pulse, PE and IVIg. MuSK- MG patients show greater incidence of dysphagia and crises compared with AChR-MG patients, and are usually considered to require earlier aggressive treatment. Reducing steroid dosage after remission is usually problematic because of the risk of relapse, and immunosuppressive agents are also less effective than in AChR-MG cases. 60 There have been more reports of the efficacy of the new treatment rituximab for intractable MuSK-MG, although in Japan this treatment is not covered by national insurance. 60,63 Treatment plans for ocular DS-MG muscle should consider the fact that the causative agent could be anti-achr antibodies in quantities below the detection limit. 57 In cases of DS-MG with thymoma, thymectomy should be carried out as in AChR-MG cases. In generalized cases without concomitant thymoma, PE/PP should be carried out as therapeutic diagnosis if clinical presentation and laboratory findings suggest MG. Treatment strategies for ocular MG Even if MG symptoms are limited to the eye muscles in the early stages of the disease, it might generalize within 2 years of onset. MG rarely generalizes more than 2 years after onset, so if symptoms are limited to ocular muscles 2 years after onset, it is appropriate to diagnose as ocular MG Immunotherapy is considered effective for ocular MG, but there is no sufficient evidence available For patients with external ophthalmoplegia sufficient to inhibit activities of daily living, steroid pulse therapy results in remission faster than standard oral steroid therapy Anticholinesterase agents are often used for symptomatic treatment, but efficacy against ocular MG is limited, with sufficient efficacy in just 20 50% of cases Naphazoline eye drops are effective for symptomatic treatment when eyelid ptosis is the only MG symptom, or when it is the only symptom persisting post-treatment One treatment option for eyelid ptosis refractory to treatment is eyelid elevation Ocular MG is often considered milder than generalized MG, but ptosis and diplopia can both impair eye function for daily activities and influence patients QOL. 64 Approximately half of MG patients show ocular MG at onset, of whom 50 60% develop generalized MG within 2 years. 65 67 Elderly patients show a slightly lower ratio of generalizing, and are more likely to have permanent ocular MG. 68 Grob et al. 10 reported that ocular symptoms reach their peak within 1 year for 70% of patients, whereas 20% of patients enter remission within 6 months. Almost all ocular MG cases that develop generalized MG do so within 1 year; just 12% do so after 1 year. Also, Bever et al. 69 reported that 85% of all cases that transition from ocular MG to generalized MG do so within 2 years. There is no rigorous, clear evidence on treatment methods for ocular MG, but steroid therapy is considered the most effective treatment based on clinical experience. 70 According to a retrospective study on efficacy of treatments for ocular MG, efficacy rates for ptosis were 50 and 86% for anticholinesterase agents and oral steroids, respectively; and for diplopia, 6.9 and 74% for anticholinesterase agents and oral steroids, respectively. 71 In particular, anticholinesterase agent monotherapy was ineffective 2015 Japanese Society for Neuroimmunology 27

Japanese guidelines for MG H. Murai against diplopia. Steroid therapy should be considered for cases where anticholinesterase agents are ineffective. There are few studies on steroid pulse therapy for ocular MG, but the approach should be considered if the patient shows clear clinical external ophthalmoplegia with inhibited activities of daily life. 72 The benefits of steroid pulse therapy include requiring only approximately 1 month to reach remission versus a normal several month timespan for oral drug treatment, and a mild long-term risk for adverse reactions. Specifically, one course of treatment consists of 500 1000 mg IV methylprednisolone infusion over 3 days. The treatment goal is normally three courses of treatment, but four to five might be carried out if efficacy is insufficient. Pulse therapy for ocular MG entails initial transient exacerbation of eye symptoms and sometimes transient limb weakness, but these do not normally reach the level of crisis, and the treatment is safer than when carried out for generalized MG. After pulse therapy, oral steroid treatment is usually initiated, followed by dose reduction and maintenance. Other immunotherapy approaches for ocular MG consist of using immunosuppressive agents based on usage methods for generalized MG. Eye drops of the a 2 -adrenoceptor stimulant, naphazoline, strengthen contraction of M uller s muscle, thereby improving some muscle disorders and eyelid ptosis resulting from partial Horner syndrome. 73 One recent multicenter joint study reported 71.7% usefulness of naphazoline eye drops against eyelid ptosis in 60 MG patients. 73 If eyelid ptosis does not respond to treatment and persists, surgery might be able to repair eyelid function and appearance. There are few studies on the long-term course after surgery or with large sample sizes, but surgery should yield good therapeutic effects as long as the case selection, timing, procedure and surgeon are all appropriate. 74 76 Treatment strategies for LOMG and elderly MG patients Ocular MG is more common in LOMG than in EOMG or TAMG Generalized LOMG responds well to immunotherapy, and the target of MM with PSL 5 mg/day or lower is easily achieved However, full remission is difficult to achieve regardless of whether or not thymectomy is carried out Thymectomy is not considered first-line treatment for LOMG, and should be considered carefully in these cases The incidence of MG in middle-aged or elderly persons has increased from the 1990s forward, and reports are beginning to come out of Europe that such cases have surpassed EOMG in frequency. 5,77 A clinical epidemiology study carried out in Japan in 2006 found an increasing number of MG patients, particularly LOMG patients. 1 Because long-term remission rates for MG are low, recently MG patients have begun to increase in age. The MG patient population has changed significantly from 20 to 30 years ago, and the majority of patients with the disease are now middle-aged or elderly. Thymus tissue in LOMG patients usually shows no difference compared with atrophic thymus of non- MG patients, so thymectomy is not a first-line treatment for non-thymomatous LOMG. Mortality rates are higher in LOMG patients than in younger patients, but this is also an effect of unrelated concomitant illnesses, adverse reactions to medications and other factors. 78 80 It can be difficult to evaluate MG symptoms in elderly patients as a result of other physical conditions or concomitant illnesses. Care is required, as delays in diagnosis or recognizing aggravated symptoms can lead to worsening of the disease. Quantitative MG evaluation instruments should be used regularly. At present there is no evidence providing a reference for optimal treatments of LOMG. LOMG patients often respond well to immunotherapy, and rates of achieving the first MG treatment goal (MM with PSL 5 mg/day or below) are higher than for EOMG or TAMG. Elderly patients often have concomitant illnesses and are particularly susceptible to adverse reactions from corticosteroids, so calcineurin inhibitors should be used concurrently in order to minimize oral steroid dosage. High-dose steroid therapy using dose-escalation and de-escalation should be avoided as much as possible. For elderly patients, IVIg is a safe and effective option for fast-acting immunotherapy, but care should be taken regarding infusion speed. Conclusion The new Japanese clinical guidelines support a philosophy of MG treatment that respect patients QOL. Reduced doses of corticosteroids are recommended, with the initial goal of the treatment set at MM with PSL 5 mg/day or below. To achieve this goal, 28 2015 Japanese Society for Neuroimmunology

H. Murai Japanese guidelines for MG early aggressive treatments, such as PE/PP, IVIg or steroid pulse therapies, are proposed. Acknowledgements The Japanese Committee of Clinical Guidelines for MG consists of the following members: Chairman: Akio Suzumura; Co-chairmen: Masakatsu Motomura and Kimiaki Utsugisawa; Committee members: Keiko Ishigaki, Tomihiro Imai, Naoki Kawaguchi, Seiji Kikuchi, Shigeaki Suzuki, Yoshiko Nomura, Makoto Matsui, Hidenori Matsuo, Hiroyuki Murai and Hiroaki Yoshikawa; Collaborators: Kazuo Iwasa, Hirokazu Shiraishi, Emiko Tsuda, Yuriko Nagane, Takashi Fukuda and Naoya Minami; Advisors: Masaharu Takamori, Yoshitaka Fujii and Teiji Yamamoto. The author wrote this review on behalf of all the members. Conflict of interest None declared. References 1. Murai H, Yamashita N, Watanabe M, et al. Characteristics of myasthenia gravis according to onset-age: Japanese nationwide survey. J Neurol Sci. 2011; 305: 97 102. 2. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol. 2010; 10: 46. 3. Matsuda M, Dohi-Iijima N, Nakamura A, et al. Increase in incidence of elderly-onset patients with myasthenia gravis in Nagano Prefecture, Japan. Intern Med. 2005; 44: 572 7. 4. Matsui N, Nakane S, Nakagawa Y, et al. Increasing incidence of elderly onset patients with myasthenia gravis in a local area of Japan. J Neurol Neurosurg Psychiatry. 2009; 80: 1168 71. 5. Somnier FE. Increasing incidence of late-onset anti-achr antibody-seropositive myasthenia gravis. Neurology. 2005; 65: 928 30. 6. Aarli JA. Myasthenia gravis in the elderly: is it different? Ann N Y Acad Sci. 2008; 1132: 238 43. 7. Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol. 2002; 2: 797 804. 8. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001; 7: 365 8. 9. Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011; 69: 418 22. 10. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008; 37: 141 9. 11. Masuda M, Utsugisawa K, Suzuki S, et al. The MG-QOL15 Japanese version: validation and associations with clinical factors. Muscle Nerve. 2012; 46: 166 73. 12. Gilhus NE. Autoimmune myasthenia gravis. Expert Rev Neurother. 2009; 9: 351 8. 13. Japanese Committee of Clinical Guidelines for Myasthenia Gravis. Japanese clinical guidelines for myasthenia gravis 2014 [In Japanese]. Nankodo, Tokyo; 2014. 14. Mittal MK, Barohn RJ, Pasnoor M, et al. Ocular myasthenia gravis in an academic neuro-ophthalmology clinic: clinical features and therapeutic response. J Clin Neuromuscul Dis. 2011; 13: 46 52. 15. Golnik KC, Pena R, Lee AG, Eggenberger ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology. 1999; 106: 1282 6. 16. Jacobson DM. The ice pack test for diagnosing myasthenia gravis. Ophthalmology. 2000; 107: 622 3. 17. Chatzistefanou KI, Kouris T, Iliakis E, et al. The ice pack test in the differential diagnosis of myasthenic diplopia. Ophthalmology. 2009; 116: 2236 43. 18. Nagane Y, Suzuki S, Suzuki N, Utsugisawa K. Early aggressive treatment strategy against myasthenia gravis. Eur Neurol. 2011; 65: 16 22. 19. Suzuki Y, Utsugisawa K, Suzuki S, et al. Factors associated with depressive state in patients with myasthenia gravis: a multicentre cross-sectional study. BMJ Open. 2011; 1: e000313. 20. Twork S, Wiesmeth S, Klewer J, Pohlau D, Kugler J. Quality of life and life circumstances in German myasthenia gravis patients. Health Qual Life Outcomes. 2010; 8: 129. 21. Burns TM. History of outcome measures for myasthenia gravis. Muscle Nerve. 2010; 42: 5 13. 22. Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity. 2010; 43: 428 35. 23. Burns TM, Grouse CK, Wolfe GI, Conaway MR, Sanders DB. The MG-QOL15 for following the health-related quality of life of patients with myasthenia gravis. Muscle Nerve. 2011; 43: 14 8. 24. Utsugisawa K, Suzuki S, Nagane Y, et al. Health-related quality of life and treatment targets in myasthenia gravis. Muscle Nerve. 2014; 50: 493 500. 25. Truhan AP, Ahmed AR. Corticosteroids: a review with emphasis on complications of prolonged systemic therapy. Ann Allergy. 1989; 62: 375 91. 26. Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2012; 12: CD002277. 27. 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: 7 15. 2015 Japanese Society for Neuroimmunology 29

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