今日の臨床サポート

重症筋無力症

著者: 鈴木重明 慶應義塾大学

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正/監修レビュー済:2021/09/15
患者向け説明資料

概要・推奨   

  1. 抗コリンエステラーゼ阻害薬は、コリン作動性クリーゼの原因となることもあり、通常ピリドスチグミン(メスチノン)60 mgから開始し、症状をみながら180~240 mg/日までにとどめておく(推奨度1)
  1. 全身型非胸腺腫MGに対する胸腺摘除術の有効性が証明された。これまでの研究成果から若年者、抗AChR抗体高値、過形成が疑われる症例が有効である(推奨度3)
  1. 胸腺腫関連MGは、MG全体の15~25%を占めている。球症状やクリーゼの頻度が高く、非胸腺腫MGに比べて重症である。またMG以外にもさまざまな自己免疫疾患を合併する可能性があり、病期の進行にかかわらず可能な限り早期に胸腺腫を摘出することが推奨されている(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
鈴木重明 : 講演料(アレクシオンファーマ)[2021年]
監修:高橋裕秀 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、抗補体療法について加筆した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 重症筋無力症 (MG)とは、神経筋接合部のアセチルコリンレセプター(AChR)に対する自己抗体が原因となる臓器特異的な自己免疫疾患である。
  1. 20~40歳代女性に好発するが、基本的には小児から高齢者まで発症し、特に高齢発症の頻度が増加傾向にある。近年、MGの治療法が確立し予後は著しく改善したが、ステロイドなどの免疫抑制薬の内服治療が必要であり、その副作用や長期間にわたるMGの管理が必要である。
  1. MGの治療には大きな変化があり、従来行われていた治療に対して再評価が必要となっており、治療法の選択も施設により差がある。
  1. 胸腺腫のないMGにおける拡大胸腺摘除術は、有効性が証明できず、現在世界的な治験が行われているところで、全身型MGすべての症例が拡大胸腺摘除術の適応とはならなくなっている。
  1. 重症筋無力症は、指定難病であり、ある一定の重症度基準を満たした場合などでは申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
病歴・診察のポイント  
  1. 神経診察で眼筋あるいは四肢近位筋の筋力低下の有無を確認する。

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文献 

著者: V Bril, J Kojic, A Dhanani
雑誌名: Neurology. 1998 Oct;51(4):1198-200.
Abstract/Text We compared 42 myasthenia gravis (MG) patients with thymoma with 42 generalized MG patients without thymoma using a modified Osserman classification. The mean Osserman grades at diagnosis, 6 months, and 5 and 10 years post-thymectomy did not differ between groups. Our results indicate that thymoma is not a negative determinant for the long-term clinical outcome of MG.

PMID 9781560  Neurology. 1998 Oct;51(4):1198-200.
著者: Y Monden, K Nakahara, S Nanjo, Y Fujii, A Matsumura, A Masaoka, Y Kawashima
雑誌名: Cancer. 1984 Dec 1;54(11):2513-8. doi: 10.1002/1097-0142(19841201)54:11<2513::aid-cncr2820541133>3.0.co;2-i.
Abstract/Text In 261 surgically treated patients with myasthenia gravis (MG), 26 had an invasive thymoma and 49 had a noninvasive thymoma. Invasive thymoma was seen in 41% of thymomatous MG patients older than 40 years of age, and 28% in patients younger than 40 years of age. Of 19 patients who underwent total or subtotal thymothymomectomy accompanied by irradiation (4000 rad), 17 were still alive on an average 6.5 years after surgery. The deterioration of MG by the irradiation was observed in 7 of 20 irradiated cases. Thus, postoperative irradiation is effective but should be done with attention to the deterioration of MG. The prognosis of MG in patients with an invasive thymoma was poorer than that in patients with a noninvasive thymoma.

PMID 6498741  Cancer. 1984 Dec 1;54(11):2513-8. doi: 10.1002/1097-014・・・
著者: Johan A Aarli
雑誌名: Ann N Y Acad Sci. 2008;1132:238-43. doi: 10.1196/annals.1405.040.
Abstract/Text We have defined myasthenia gravis (MG) in the elderly as onset after the age of 50 years. MG is diagnosed more often today than previously. The increase is mainly found in patients over the age of 50 years. Neurologists therefore see more old patients with MG now than before. Prevalence of the early-onset form of MG seems to be unchanged. Recent data indicate that MG may still be substantially underdiagnosed in very old people. Ptosis, diplopia, weakness of the facial muscles, and problems of articulation are important clinical signs in MG and are easier to detect in a youthful appearance. Since ageing causes a decrease in the total eyelid area with sagging of the lower eyelids, a ptosis may be more difficult to diagnose in the elderly. In addition, diplopia may not be detected because of reduced vision due to macular degeneration or cataract formation. Ocular symptoms of MG are therefore more easily missed in the elderly. Thymomatous MG is more common among older patients than it is in younger onset. The mean age at onset of MG for thymoma cases is 50-60 years. Approximately 10-15% of all MG patients have a thymoma, and around 40% of all thymoma cases are associated with MG. During normal aging, the thymus tissue becomes atrophic and replaced with fat. Recent data on MG thymus pathology suggest that lymphocyte accumulation indicating residual thymus may also be found in the elderly, and that there is little qualitative difference between the young and the old thymus from MG patients. The mean concentration of antibodies to acetylcholine receptor (AChR) is lower in MG in the elderly than in early-onset or thymoma-associated MG. Seronegative MG is less common among older patients. Approximately 30% of patients with late-onset, nonthymoma MG have antibodies to titin, while such antibodies are extremely scarce in early-onset MG. Titin antibodies in MG patients seem to be associated with a higher frequency of DR7 antigen and a decrease of DR3 antigen. The antibody response in MG may therefore be influenced by the genetic background.

PMID 18567874  Ann N Y Acad Sci. 2008;1132:238-43. doi: 10.1196/annals・・・
著者: Hiroyuki Murai, Natsumi Yamashita, Makoto Watanabe, Yoshiko Nomura, Masakatsu Motomura, Hiroaki Yoshikawa, Yosikazu Nakamura, Naoki Kawaguchi, Hiroshi Onodera, Shigeru Araga, Noriko Isobe, Masaki Nagai, Jun-ichi Kira
雑誌名: J Neurol Sci. 2011 Jun 15;305(1-2):97-102. doi: 10.1016/j.jns.2011.03.004. Epub 2011 Mar 26.
Abstract/Text OBJECTIVE: To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan.
METHODS: We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships.
RESULTS: A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively.
CONCLUSIONS: Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan.

Copyright © 2011 Elsevier B.V. All rights reserved.
PMID 21440910  J Neurol Sci. 2011 Jun 15;305(1-2):97-102. doi: 10.1016・・・
著者: Gil I Wolfe, Henry J Kaminski, Inmaculada B Aban, Greg Minisman, Hui-Chien Kuo, Alexander Marx, Philipp Ströbel, Claudio Mazia, Joel Oger, J Gabriel Cea, Jeannine M Heckmann, Amelia Evoli, Wilfred Nix, Emma Ciafaloni, Giovanni Antonini, Rawiphan Witoonpanich, John O King, Said R Beydoun, Colin H Chalk, Alexandru C Barboi, Anthony A Amato, Aziz I Shaibani, Bashar Katirji, Bryan R F Lecky, Camilla Buckley, Angela Vincent, Elza Dias-Tosta, Hiroaki Yoshikawa, Márcia Waddington-Cruz, Michael T Pulley, Michael H Rivner, Anna Kostera-Pruszczyk, Robert M Pascuzzi, Carlayne E Jackson, Guillermo S Garcia Ramos, Jan J G M Verschuuren, Janice M Massey, John T Kissel, Lineu C Werneck, Michael Benatar, Richard J Barohn, Rup Tandan, Tahseen Mozaffar, Robin Conwit, Joanne Odenkirchen, Joshua R Sonett, Alfred Jaretzki, John Newsom-Davis, Gary R Cutter, MGTX Study Group
雑誌名: N Engl J Med. 2016 Aug 11;375(6):511-22. doi: 10.1056/NEJMoa1602489.
Abstract/Text BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.
METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.
RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003).
CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

PMID 27509100  N Engl J Med. 2016 Aug 11;375(6):511-22. doi: 10.1056/N・・・
著者: K D Sethi, D C Hess, V H Huffnagle, R J Adams
雑誌名: Neurology. 1992 Apr;42(4):919-21.
Abstract/Text We report successful treatment of paroxysmal dystonia (tonic seizures) in three patients with central demyelinating disease (CDD) using acetazolamide alone or in combination with carbamazepine. Acetazolamide is a useful alternative, or an adjunct, to carbamazepine in the treatment of paroxysmal dystonia in CDD.

PMID 1565252  Neurology. 1992 Apr;42(4):919-21.
著者: A Sghirlanzoni, D Peluchetti, R Mantegazza, F Fiacchino, F Cornelio
雑誌名: Neurology. 1984 Feb;34(2):170-4.
Abstract/Text We have evaluated chronic corticosteroid treatment in 60 myasthenic patients; 92% were followed for more than 3 years and 82% longer than 4 years. Improvement was noted in 72% of the patients. The best results were seen in those whose symptoms started after the age of 40 years. There was a correlation between the starting dose of prednisone and the rate of improvement. Complete withdrawal of steroids was possible only for 3 patients.

PMID 6538004  Neurology. 1984 Feb;34(2):170-4.
著者: W Hoch, J McConville, S Helms, J Newsom-Davis, A Melms, A Vincent
雑誌名: Nat Med. 2001 Mar;7(3):365-8. doi: 10.1038/85520.
Abstract/Text Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.

PMID 11231638  Nat Med. 2001 Mar;7(3):365-8. doi: 10.1038/85520.
著者: Matthew N Meriggioli, Donald B Sanders
雑誌名: Lancet Neurol. 2009 May;8(5):475-90. doi: 10.1016/S1474-4422(09)70063-8.
Abstract/Text Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which patients experience fluctuating skeletal muscle weakness that often affects selected muscle groups preferentially. The target of the autoimmune attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the neuromuscular junction, such as the muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological result is muscle endplate dysfunction and consequent fatigable muscle weakness. Clinical presentations vary substantially, both for anti-AChR positive and negative MG, and accurate diagnosis and selection of effective treatment depends on recognition of less typical as well as classic disease phenotypes. Accumulating evidence suggests that clinical MG subgroups might respond differently to treatment. In this Review, we provide current information about the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and treatment of MG, including emerging therapeutic strategies.

PMID 19375665  Lancet Neurol. 2009 May;8(5):475-90. doi: 10.1016/S1474・・・
著者: C S Hudson, J E Rash, T N Tiedt, E X Albuquerque
雑誌名: J Pharmacol Exp Ther. 1978 May;205(2):340-56.
Abstract/Text Brief and chronic exposure of rats to neostigmine methylsulfate produced marked morphological alterations of the fine structure at the end-plate region of the extensor digitorum longus muscles. These changes were dose and time dependent and were restricted primarily to the subjunctional myofibrillar apparatus and membrane-bound organelles. In addition, significant presynaptic alterations were observed including synaptic vesicle depletion and the appearance of numerous coated vesicles and membrane cisternae, which indicated continuing nerve terminal hyperactivity. With chronic treatment, degeneration and partial recovery of the nerve axon also were observed. The morphological changes of the end-plate region induced by neostigmine did not occur in most fibers after brief denervation and were eliminated entirely by chronic nerve section. Thus, the postsynaptic degenerative changes caused by neostigmine treatment observed in nondenervated animals appear to result primarily from greatly increased synaptic activity and not primarily from a direct neostigmine reaction with the pre- or postsynaptic membranes. Since the myopathic changes observed in this study were produced by neostigmine, a drug which is commonly employed in the routine treatment of human patients with myasthenia gravis, continued use of neostigmine for long-term therapy in noncrisis situations may not be accepted as being free from risk.

PMID 641832  J Pharmacol Exp Ther. 1978 May;205(2):340-56.
著者: T L Munsat
雑誌名: J Neurol Sci. 1984 Apr;64(1):5-10.
Abstract/Text
PMID 6376715  J Neurol Sci. 1984 Apr;64(1):5-10.
著者: C E Thomas, S A Mayer, Y Gungor, R Swarup, E A Webster, I Chang, T H Brannagan, M E Fink, L P Rowland
雑誌名: Neurology. 1997 May;48(5):1253-60.
Abstract/Text We retrospectively reviewed the hospital records of 53 patients admitted for 73 episodes of myasthenic crisis at Columbia-Presbyterian Medical Center over a period of 12 years, from 1983 to 1994. Median age at the onset of first crisis was 55 (range, 20 to 82), the ratio of women to men was 2:1, and the median interval from onset of symptoms to first crisis was 8 months. Infection (usually pneumonia or upper respiratory infection) was the most common precipitating factor (38%), followed by no obvious cause (30%) and aspiration (10%). Twenty-five percent of patients were extubated at 7 days, 50% at 13 days, and 75% at 31 days; the longest crisis exceeded 5 months. Using survival analysis and backward stepwise Cox regression, we identified three independent predictors of prolonged intubation: (1) pre-intubation serum bicarbonate > or = 30 mg/dl (p = 0.0004, relative hazard 4.5), (2) peak vital capacity day 1 to 6 post-intubation < 25 ml/kg (p = 0.001, relative hazard 2.9), and (3) age > 50 (p = 0.01, relative hazard 2.4). The proportion of patients intubated longer than 2 weeks was 0% among those with no risk factors, 21% with one risk factor, 46% with two risk factors, and 88% with three risk factors (p = 0.0004). Complications independently associated with prolonged intubation included atelectasis (p = 0.002), anemia treated with transfusion (p = 0.03), Clostridium difficile infection (p = 0.01), and congestive heart failure (p = 0.03). Three episodes of crisis were fatal, for a mortality rate of 4% (3/73); four additional patients died after extubation. All seven deaths were due to overwhelming medical comorbidity. Over half of those who survived were functionally dependent (home or institutionalized) at discharge. In addition to prospective controlled studies of immunotherapies, the prevention and treatment of medical complications offers the best opportunity for further improving the outcome of myasthenic crisis.

PMID 9153452  Neurology. 1997 May;48(5):1253-60.
著者: J D Mann, T R Johns, J F Campa
雑誌名: Neurology. 1976 Aug;26(8):729-40.
Abstract/Text Favorable results were obtained in 30 patients with myasthenia gravis treated initially with high daily doses of prednisone and subsequently maintained on lower doses for a protracted period. In 45 incidents of treatment, complete remission occurred in 69 percent, marked improvement in 20 percent, and moderate improvement in 17 percent. Nineteen patients proceeded to thymectomy, with negligible morbidity and sustained improvement. In four patients, it was possible to discontinue prednisone 1 year or more after thymectomy.

PMID 821005  Neurology. 1976 Aug;26(8):729-40.
著者: R M Pascuzzi, H B Coslett, T R Johns
雑誌名: Ann Neurol. 1984 Mar;15(3):291-8. doi: 10.1002/ana.410150316.
Abstract/Text One hundred sixteen patients, aged 8 to 82 years, with myasthenia gravis were treated with prednisone, 60 to 80 mg daily, until the onset of improvement, followed by lower-dose alternate-day therapy of several years' duration. Of all patients, 80.2% achieved either remission (27.6%) or marked improvement (52.6%). Moderate improvement occurred in 14.7%, and 5.2% showed no improvement. Increasing age correlated with a favorable outcome, but sex, duration of illness prior to treatment, severity and distribution of weakness at the time of onset of treatment, and presence of thymoma were not factors in the response to therapy.

PMID 6721451  Ann Neurol. 1984 Mar;15(3):291-8. doi: 10.1002/ana.4101・・・
著者: C Lindberg, O Andersen, A K Lefvert
雑誌名: Acta Neurol Scand. 1998 Jun;97(6):370-3.
Abstract/Text OBJECTIVES: To evaluate the efficacy and safety of one single intravenous methylprednisolone (IVMP) pulse therapy in myasthenia gravis.
MATERIAL AND METHODS: We performed a double blind placebo controlled study (2+2 g IVMP vs placebo) in patients with moderate MG.
RESULTS: A mean increase in muscle function of 27 points was found in the treatment group after one IVMP pulse as compared with a 0.7 point increase in the placebo group (P<0.01). In the IVMP group 8 of 10 patients showed a positive treatment response. The mean duration of improvement after IVMP was 8 weeks (range 4-14 weeks). No severe side effects were found. Acetylcholine receptor antibody concentrations were unchanged in spite of the positive treatment response.
CONCLUSIONS: We conclude that a single IVMP treatment is efficacious and safe in the treatment of moderate MG.

PMID 9669469  Acta Neurol Scand. 1998 Jun;97(6):370-3.
著者: E Arsura, N G Brunner, T Namba, D Grob
雑誌名: Arch Neurol. 1985 Dec;42(12):1149-53.
Abstract/Text Corticosteroids have been useful in the management of myasthenia gravis (MG), but their efficacy has been limited by the slow onset of improvement, initial worsening of MG, refractoriness of some patients, and side effects of large daily doses. High-dose intravenous methylprednisolone pulses have been reported to produce rapid improvement in several immunologic disorders. In this study we administered 2 g of methylprednisolone intravenously every five days to 15 consecutive patients who had exacerbation of generalized MG. Satisfactory improvement occurred in ten of 15 patients after two courses and in two of five patients after a third course. Onset of improvement began a mean (+/- SD) of 3 +/- 1.1 days after the first infusion, 2.1 +/- 1 days after the second, and 2.4 +/- 1 days after the third, and reached its maximum level 8.9 +/- 6.1 days after the last infusion. A decrease in strength occurred in three patients 1.43 +/- 1.30 days after each infusion, was not marked, and lasted three days, following which improvement generally occurred. Side effects were minimal. After improvement, a daily dose of prednisone (30 mg) was used to maintain improvement. Use of pulse therapy at five-day intervals for the management of severe MG seems to have an advantage in that it produces less initial worsening and more rapid improvement in MG, enabling smaller daily maintenance doses to be employed, with fewer side effects.

PMID 4062612  Arch Neurol. 1985 Dec;42(12):1149-53.
著者: M J Kupersmith, M Moster, S Bhuiyan, F Warren, H Weinberg
雑誌名: Arch Neurol. 1996 Aug;53(8):802-4.
Abstract/Text OBJECTIVE: To determine if moderate-or low-dose corticosteroid therapy can reduce the diplopia and frequency of deterioration to generalized disease in ocular myasthenia gravis.
DESIGN: Retrospective record review.
SETTING: Two university-based neuro-ophthalmology services.
PATIENTS: All 32 patients with ocular myasthenia gravis, treated with prednisone, followed up for a minimum of 2 years were included. Patients were treated with 1 or more courses of daily prednisone (highest initial dose, 40-80 mg) gradually withdrawn over 4 to 6 weeks. Subsequently, in 6 patients, 2.5 to 20 mg of prednisone was given on alternate day.
OUTCOME MEASURES: Diplopia in the primary position or downgaze diplopia and generalized myasthenia gravis after 2 years of follow-up.
RESULTS: Diplopia, which was initially found in the primary position in 29 patients and in the downgaze position in 26 patients, was absent in 21 patients at 2 years. Generalized myasthenia gravis occurred in 3 patients at 2 years. Elevated serum acetylcholine receptor antibody levels and abnormal electromyography findings were not predictive of worsening. No patient experienced a major steroid complication.
CONCLUSIONS: Moderate-dose daily prednisone for 4 to 6 weeks, followed by low-dose alternate-day therapy as needed, can control the diplopia in patients with ocular myasthenia gravis. The frequency of deterioration to generalized myasthenia gravis at 2 years may be reduced; 9.4% in this study compared with more than 40% previously reported frequency. Corticosteroids may be useful even when ocular motor dysfunction is not normalized.

PMID 8759987  Arch Neurol. 1996 Aug;53(8):802-4.
著者: N Sommer, B Sigg, A Melms, M Weller, K Schepelmann, V Herzau, J Dichgans
雑誌名: J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):156-62.
Abstract/Text OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options.
METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years.
RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%).
CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.

PMID 9048716  J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):156-62.
著者: Yuriko Nagane, Kimiaki Utsugisawa, Shigeaki Suzuki, Masayuki Masuda, Yuko Shimizu, Hiroya Utsumi, Shinichiro Uchiyama, Norihiro Suzuki
雑誌名: Muscle Nerve. 2011 Jul;44(1):41-4. doi: 10.1002/mus.22002. Epub 2011 Apr 12.
Abstract/Text INTRODUCTION: When treating ocular myasthenia gravis (MG), the risk/benefit profile of corticosteroids is unclear, and acetylcholinesterase inhibitors are not very effective. We examined the efficacy of topical naphazoline in the treatment of myasthenic blepharoptosis.
METHODS: Sixty MG patients with blepharoptosis (32 with ocular symptoms only and 28 with mild generalized symptoms) were enrolled in a multicenter open trial of topical naphazoline. The effects were reported by patients via a questionnaire and were also confirmed for each patient at the clinic.
RESULTS: Among 70 eyes of 60 patients, 20 eyes (28.6%) of 17 patients (28.3%) exhibited a marked response (full eye opening), and 24 eyes (34.3%) of 20 patients (33.3%) showed a good response (adequate but incomplete eye opening). Topical naphazoline was evaluated as useful in the treatment of myasthenic blepharoptosis by >70% of the patients.
CONCLUSIONS: Topical naphazoline was found to be an effective supplementary symptomatic treatment for myasthenic blepharoptosis.

Copyright © 2011 Wiley Periodicals, Inc.
PMID 21491460  Muscle Nerve. 2011 Jul;44(1):41-4. doi: 10.1002/mus.220・・・
著者: R S Tindall, J T Phillips, J A Rollins, L Wells, K Hall
雑誌名: Ann N Y Acad Sci. 1993 Jun 21;681:539-51.
Abstract/Text We randomly assigned 39 patients with steroid-dependent generalized myasthenia gravis to treatment with cyclosporine (5 mg/kg per body weight in divided doses) or placebo. Duration of treatment was 6 months. Patients were evaluated monthly. Primary measures of efficacy were quantified strength testing, antihuman acetylcholine receptor antibody titer, and dosage of corticosteroid medication. At the end of the study, patients in the cyclosporine group had significantly greater improvement in strength (p = 0.004) and a reduction in antireceptor antibody titer (p = 0.01). Percentage reduction of steroid medication was greater in the cyclosporine group, although the difference was not statistically significant (p = 0.12). There were no treatment failures, and there was one drug failure in the cyclosporine group. In the placebo group, there were three treatment failures. No significant nephrotoxicity was noted at this dosage during the first 6 months. During the subsequent 18 months of open-label therapy, continued reduction in steroid dosage occurred. Cumulative side effects, however, caused 35% of patients to discontinue the medication; 10% did so secondary to slowly progressive nephrotoxicity.

PMID 8357194  Ann N Y Acad Sci. 1993 Jun 21;681:539-51.
著者: J Palace, J Newsom-Davis, B Lecky
雑誌名: Neurology. 1998 Jun;50(6):1778-83.
Abstract/Text We compared prednisolone (PRED) and azathioprine (AZA) versus prednisolone alone in the treatment of MG. Prednisolone alone or combined with azathioprine is widely used in the treatment of MG, but no randomized placebo-controlled comparative trial data are available. The prednisolone dose and clinical outcome were compared in a multicenter randomized double-blind study of 34 MG patients who were followed up for 3 years. One group (PRED + AZA) received prednisolone (on alternate days) plus azathioprine (2.5 mg/kg); the other group received prednisolone on alternate days plus placebo (PRED + PLAC). Initial high-dose prednisolone (1.5 mg/kg on alternate days) was tapered at remission to the minimal dose required to maintain remission. The prednisolone dose did not differ significantly between the two groups at 1 year (median values: PRED + AZA, 37.5 mg on alternate days; PRED + PLAC, 45 mg on alternate days) but was reduced at 2 and 3 years in the PRED + AZA group (median value at 3 years: PRED + AZA, 0 mg on alternate days; PRED + PLAC, 40 mg on alternate days; p=0.02). Relapses and failures to remit over the 3 years were more frequent in the PRED + PLAC group. There was a sharp rise in the anti-acetylcholine receptor (AChR) titers in the PRED + PLAC group at 2 years. Incidence of side effects was slightly less in the PRED + AZA group. Azathioprine as an adjunct to alternate day prednisolone in the treatment of antibody-positive generalized MG reduces the maintenance dose of prednisolone and is associated with fewer treatment failures, longer remissions, and fewer side effects.

PMID 9633727  Neurology. 1998 Jun;50(6):1778-83.
著者: K Utsugisawa, Y Nagane, S Suzuki, N Suzuki
雑誌名: Eur J Neurol. 2008 Jun;15(6):598-604. doi: 10.1111/j.1468-1331.2008.02130.x. Epub 2008 Apr 9.
Abstract/Text PURPOSE: To examine whether the monitoring of cyclosporine (CsA) blood concentrations is of benefit in CsA microemulsion pre-concentrate (MEPC) therapy for myasthenia gravis (MG).
METHODS: We measured CsA blood concentrations both 2 h after administration (C2) and immediately before administration (C0) and examined associations with changes to clinical parameters in 20 MG patients treated with CsA MEPC in an unblinded, 6-month prospective open trial.
RESULTS: Initial dose of CsA MEPC (4.7 +/- 0.5 mg/kg/day) provided both high C2 levels and safe C0 levels. Disease severity, daily dose of prednisolone, acetylcholine receptor-antibody titre levels and levels of interleukin-2 production by peripheral blood mononuclear cells were significantly reduced following treatment with CsA MEPC. A significant correlation existed between C2 levels following the initial dose and clinical improvement in responder MG patients. C0 levels were significantly higher in patients who exhibited increased serum creatinine or hypertension compared with patients free from side effects. Body mass index of individual patients was significantly correlated with C0 level, and may thus offer a useful marker to predict C0 levels.
DISCUSSION: CsA MEPC was effective at suppressing symptoms and T-cell-dependent pathogenesis of MG, and monitoring of C2 and C0 levels can be useful to estimate efficacy and safety of the drug.

PMID 18410372  Eur J Neurol. 2008 Jun;15(6):598-604. doi: 10.1111/j.14・・・
著者: Hiroaki Yoshikawa, Takahiro Kiuchi, Takahiko Saida, Masaharu Takamori
雑誌名: J Neurol Neurosurg Psychiatry. 2011 Sep;82(9):970-7. doi: 10.1136/jnnp-2011-300148. Epub 2011 Jul 22.
Abstract/Text OBJECTIVES: To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study.
METHODS: Patients being treated with oral prednisolone at doses equivalent to 10-20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study.
RESULTS: Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p = 0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted.
CONCLUSIONS: This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients.
CLINICAL TRIAL REGISTRATION NUMBER: NCT00309088. Name of the trial registry: FK506 Phase 3 STUDY: A STUDY for Steroid Non-Resistant MG Patients.

PMID 21784757  J Neurol Neurosurg Psychiatry. 2011 Sep;82(9):970-7. do・・・
著者: N Shibuya, T Sato, M Osame, T Takegami, S Doi, S Kawanami
雑誌名: J Neurol Neurosurg Psychiatry. 1994 May;57(5):578-81.
Abstract/Text The results of a multicentre trial were analysed to evaluate the efficacy of immunoadsorption therapy for severe generalised myasthenia gravis. Twenty patients with myasthenia gravis who were concurrently receiving high dose prednisolone and azathioprine therapy were treated with an affinity-type adsorbent, using tryptophan-linked polyvinyl alcohol gel (IM-TR), according to a standardised treatment protocol. The 20 patients received five adsorption treatments within a period of 10 days. In 11, pronounced improvement of myasthenic weakness was seen and long-term remission was maintained. The treatment was especially effective in patients with thymic hyperplasia. Circulating acetylcholine receptor (AChR) antibodies were reduced by about 60% by treating one plasma volume. There was no difference in the rate of removal of the AChR antibodies between patients with thymic hyperplasia and patients with thymoma. No serious complications occurred during 100 procedures. It was concluded that the immunoadsorption therapy with IM-TR is useful in controlling symptoms in patients with severe myasthenia gravis who are otherwise unresponsive.

PMID 8201327  J Neurol Neurosurg Psychiatry. 1994 May;57(5):578-81.
著者: D Grob, D Simpson, H Mitsumoto, B Hoch, F Mokhtarian, A Bender, M Greenberg, A Koo, S Nakayama
雑誌名: Neurology. 1995 Feb;45(2):338-44.
Abstract/Text We treated 16 patients with moderately severe to severe generalized myasthenia gravis (MG) by immunoadsorption (perfusion through a resin that adsorbs proteins) of 2,500 ml plasma on each of four alternate days. Fourteen patients who completed treatment all had significant improvement in strength (6 excellent, 6 good, and 2 fair), which began a mean of 42 hours after the first immunoadsorption, reached a maximum 4 days after the fourth immunoadsorption (mean, 250% of baseline strength), and returned to baseline over a mean of 2 months. Thirty-seven grams of plasma proteins were removed during each immunoadsorption, which required no replacement, compared with 175 grams during plasma exchange, which requires replacement with albumin. Serum or plasma concentration of all proteins fell, more so for most of the larger proteins than for the smaller ones: acetylcholine receptor antibody (AChR Ab) fell to a mean of 23% of original level, fibrinogen to 26%, C4 to 29%, IgM to 33%, IgG to 35%, CH50 to 41%, C3 to 42%, IgA to 54%, and albumin to 76%. All proteins, including AChR Ab, returned to their original levels within 1 to 3 weeks after the last immunoadsorption, while improvement in strength lasted a mean of 6 weeks longer. One seronegative patient had excellent improvement lasting more than a month. Activated complement C5a and white blood cell count rose during each immunoadsorption, while activated complement C3a fell, and each returned to its original level within hours. Eight patients had transient symptomatic hypotension attributable to withdrawal of blood more rapidly than it was returned; this hypotension was prevented or ameliorated by intravenous saline.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7854536  Neurology. 1995 Feb;45(2):338-44.
著者: P Gajdos, S Chevret, B Clair, C Tranchant, C Chastang
雑誌名: Ann Neurol. 1997 Jun;41(6):789-96. doi: 10.1002/ana.410410615.
Abstract/Text We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (i.v.Ig) or plasma exchange (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of i.v.Ig. Eighty-seven patients with MG exacerbation were randomized to receive either three PE (n = 41), or i.v.Ig (n = 46) 0.4 gm/kg daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median value, +18 in the PE group and +15.5 in the i.v.Ig group, p = 0.65). Similar efficacy, although slightly reduced in the 5-day group was observed with both i.v.Ig schedules. The tolerance of i.v.Ig was better than that of PE with a total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the i.v.Ig group (p = 0.01). Although our trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for i.v.Ig. i.v.Ig is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however, could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with i.v.Ig and to determine the optimal dosage of i.v.Ig.

PMID 9189040  Ann Neurol. 1997 Jun;41(6):789-96. doi: 10.1002/ana.410・・・
著者: A I Qureshi, M A Choudhry, M S Akbar, Y Mohammad, H C Chua, A M Yahia, J A Ulatowski, D A Krendel, R T Leshner
雑誌名: Neurology. 1999 Feb;52(3):629-32.
Abstract/Text We performed a retrospective multicenter chart review to compare the efficacy and tolerance of plasma exchange (PE) and intravenous immunoglobulin (i.v.Ig) in treatment of 54 episodes of myasthenic crisis. After adjustment for other variables, PE (compared with i.v.Ig) was associated with a superior ventilatory status at 2 weeks (partial F = 6.2, p = 0.02) and 1 month functional outcome (partial F = 4.5, p = 0.04). However, the complication rate was higher with PE compared with i.v.Ig (13 versus 5 episodes, p = 0.07).

PMID 10025801  Neurology. 1999 Feb;52(3):629-32.
著者: R B Stricker, B J Kwiatkowska, J A Habis, D D Kiprov
雑誌名: Arch Neurol. 1993 Aug;50(8):837-40.
Abstract/Text Myasthenic crisis is a potentially life-threatening complication of myasthenia gravis that requires aggressive therapy. We describe four patients in whom myasthenic crisis developed and who failed to respond to initial treatment with intravenous gamma-globulin. All four patients subsequently responded to intensive plasma exchange. Based on our experience, plasmapheresis appears to be superior to intravenous gamma-globulin for the treatment of myasthenic crisis in certain patients. Prognostic factors that determine the effectiveness of intravenous gamma-globulin vs plasmapheresis in these patients merit further investigation.

PMID 8352670  Arch Neurol. 1993 Aug;50(8):837-40.

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